CN104292142B - A kind of de- aryl method of N- aryl-heterocyclic butane - Google Patents
A kind of de- aryl method of N- aryl-heterocyclic butane Download PDFInfo
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- CN104292142B CN104292142B CN201310298375.6A CN201310298375A CN104292142B CN 104292142 B CN104292142 B CN 104292142B CN 201310298375 A CN201310298375 A CN 201310298375A CN 104292142 B CN104292142 B CN 104292142B
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- hydroxy azetidine
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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 invention discloses a kind of N- aryl-heterocyclic butane to take off aryl method, comprising the following steps: in organic solvent by 1- benzyl -3- hydroxy azetidine or the dissolution of 1- benzhydryl -3- hydroxy azetidine, is cooled to -10~0 DEG C；The chloroformate -1-chloro-ethyl ester of 1.1~2.1 equivalents is slowly added dropwise in step 1 acquired solution；Step 2 acquired solution is heated to 50~80 DEG C, is reacted 1~3 hour, evaporating solvent under reduced pressure obtains first step product；First step product is dissolved in 5 times of amount methanol, at room temperature stirring and dissolving, is heated to 60~65 DEG C, back flow reaction 1~2 hour；By step 2 acquired solution evaporating solvent under reduced pressure, acetone is added, stirs 1h, filtering；By the concentration of filtrate decompression obtained by step 3, petroleum ether and stirring is added, cooling crystallization obtains white solid, i.e. 3- hydroxy azetidine hydrochloride.Present device requirement is low, and the time is short, high production efficiency, and at low cost, products obtained therefrom is superior in quality.
Description
Technical field
The invention belongs to organic drug synthesis technical field, it is de- to be related to aryl in the synthesis of N- aryl-heterocyclic butane compounds
Go the preparation of method and N- azetidine class compound.
Background technique
Azetidin compounds are as medicine intermediate, since it is with good pharmaceutical activity, in recent years by by
Gradually pay attention to and largely uses.Such as 3- aminoazetidine and 3- hydroxy azetidine and its derivative, they are synthesis
The important intermediate of antidepression and antibiotic.
Wherein 3- hydroxy azetidine hydrochloride is the important intermediate for synthesizing tebipenem pivoxil, anti-by multistep by it
Tebipenem pivoxil should be finally obtained.Tebipenem pivoxil is used for the pneumonia of paediatrics, tympanitis, nasosinusitis, to pneumococcus, including it is resistance to
The streptococcus pneumonia of Macrocyclolactone lactone kind medicine and the pneumococcus of penicillin resistant have more potent fruit, and it belongs to oral carbon mould
Carbapenem antibiotic facilitates administration route, is one of the outstanding drug of children's antibiotic medication upgrading.
Preparation to 3- hydroxy azetidine hydrochloride, document report be with 1- benzyl -3- hydroxy azetidine or
1- benzhydryl -3- hydroxy azetidine is raw material, be made by hydrogenation (US20030229226,
CN102827052).But hydrogenation is long there are the reaction time, and side reaction is more, and there are certain difficulties for purifying products, and column is needed to chromatograph,
And precious metal palladium is used, price is partially expensive, so that the industrialization of the product is met difficulty.Therefore one period of research and development is short, at low cost,
Easy-to-use synthetic route is come to prepare 3- hydroxy azetidine be the purpose of the present invention.
Summary of the invention
The object of the present invention is to provide a kind of benzyls or hexichol first using chloroformate -1-chloro-ethyl ester substituted aryl group
Base, reheating sloughs formic acid esters and then a step obtains the new method of 3- hydroxy azetidine hydrochloride, can overcome existing hydrogen
The deficiency of change technology has equipment requirement low, and the time is short, high production efficiency, at low cost, the 3- hydroxy azetidine salt of generation
The advantages that hydrochlorate is high-quality.
A kind of technical solution of the present invention: de- aryl method of N- aryl-heterocyclic butane, which is characterized in that including following step
It is rapid:
Step 1: 1- benzyl -3- hydroxy azetidine or 1- benzhydryl -3- hydroxy azetidine have been dissolved in
In solvent, it is cooled to -10~0 DEG C；
Step 2: the chloroformate -1-chloro-ethyl ester of 1.1~2.1 equivalents is slowly added dropwise in step 1 acquired solution；
Step 3: step 2 acquired solution is heated to 50~80 DEG C, is reacted 1~3 hour, evaporating solvent under reduced pressure obtains
First step product；
Step 4: first step product being dissolved in 5 times of amount methanol, at room temperature stirring and dissolving, is heated to 60~65 DEG C, reflux
Reaction 1~2 hour；
Step 5: by step 2 acquired solution evaporating solvent under reduced pressure, being added acetone, stirs 1h, filtering；
Step 6: filtrate decompression obtained by step 3 is concentrated, and petroleum ether and stirring is added, and cooling crystallization obtains white solid,
That is 3- hydroxy azetidine hydrochloride.
Preferably, organic solvent described in step 1 is 1,2- dichloroethanes, toluene, one in Isosorbide-5-Nitrae-dioxane
Kind.
Preferably, the reaction equivalent of chloroformate -1-chloro-ethyl ester described in step 2 is 1.1~2.1 times of reaction raw materials.
Preferably, the reaction temperature when chloroformate -1-chloro-ethyl ester of 1.1~2.1 equivalents being slowly added dropwise described in step 2
Degree is 0 DEG C or less.
Preferably, crystallization system described in step 6 is acetone and petroleum ether mixed solution.
Specific synthetic route of the invention is as follows:
Wherein R is represented
Beneficial effects of the present invention: it present invention uses a new synthetic route, avoids using relatively relatively hazardous
Palladium carbon hydrogenation technique is suitble to amplification production, and process equipment is simple, easily operated, short the time required to every step reaction, improves efficiency,
Raw materials used simplicity is easy to get simultaneously, cheap, also reduces cost, end product quality purity >=98.0% is superior in quality.
Specific embodiment
To keep technical problems to be solved by the inivention, technical solution and advantage clearer, below in conjunction with specific embodiment
It is described in detail.
Embodiment 1
1- benzyl -3- hydroxy azetidine 100g (0.61mol) is added in 2L reaction flask, 1,2- dichloroethanes
1000ml stirs dissolved clarification, is cooled to -5 DEG C, 130g chloroformate -1-chloro-ethyl ester (0.91mol) is dissolved in 100ml1, bis- chloroethene of 2-
It in alkane, is slowly added dropwise in Xiang Shangshu solution, control temperature is no more than 0 DEG C during being added dropwise, and continues to temperature after being added dropwise
Then reaction 10 minutes is slowly ramped to 70 DEG C, continue to react 1 hour at this temperature, HPLC monitors end of reaction, cools down,
45 DEG C are concentrated to dryness, and obtain product 108.1g, and HPLC detects purity 98.8%, yield 98.3%.
Upper step product is put into 540ml methanol, dissolved clarification is stirred at room temperature, is gradually heated to 65 DEG C, back flow reaction 1 is small
When, HPLC monitors end of reaction, removes methanol under reduced pressure, is down to room temperature, and 300ml acetone is added, and stirs 1h, filtering, filtrate decompression
It is concentrated into original volume 1/3, is down to room temperature, 200ml petroleum ether is added, crystallisation by cooling obtains white solid 60g, i.e. 3- hydroxyl azepine
Cyclobutane hydrochloride, HPLC detect purity 98%, yield 91.1%.
Embodiment 2
1- benzyl -3- hydroxy azetidine 100g (0.61mol) is added in 2L reaction flask, toluene 1000ml is stirred molten
Clearly, -5 DEG C are cooled to, 130g chloroformate -1-chloro-ethyl ester (0.91mol) is dissolved in 100ml toluene, in Xiang Shangshu solution slowly
It is added dropwise, control temperature is no more than 0 DEG C during being added dropwise, and thermotonus is continued to after being added dropwise 10 minutes, then slowly risen
Temperature continues to react 1 hour at this temperature, HPLC monitors end of reaction, and cooling, 45 DEG C are concentrated to dryness, and obtain to 70 DEG C
Product 106.5g, HPLC detect purity 98.1%, yield 96.8%.
Upper step product is put into 530ml methanol, dissolved clarification is stirred at room temperature, is gradually heated to 65 DEG C, back flow reaction 1 is small
When, HPLC monitors end of reaction, removes methanol under reduced pressure, is down to room temperature, and 300ml acetone is added, and stirs 1h, filtering, filtrate decompression
It is concentrated into original volume 1/3, is down to room temperature, 200ml petroleum ether is added, crystallisation by cooling obtains white solid 58.6g, i.e. 3- hydroxyl nitrogen
Azetidine hydrochloride, HPLC detect purity 98.2%, yield 90.1%.
Embodiment 3
1- benzhydryl -3- hydroxy azetidine 100g (0.42mol) is added in 2L reaction flask, 1,2- dichloroethanes
1000ml stirs dissolved clarification, is cooled to -5 DEG C, 108g chloroformate -1-chloro-ethyl ester (0.76mol) is dissolved in 80ml1,2- dichloroethanes
In, it is slowly added dropwise in Xiang Shangshu solution, control temperature is no more than 0 DEG C during being added dropwise, and it is anti-to continue to temperature after being added dropwise
It answers 10 minutes, is then slowly ramped to 70 DEG C, continue to react 2 hours at this temperature, HPLC monitors end of reaction, cools down, 45
It DEG C is concentrated to dryness, obtains product 73.5g, HPLC detects purity 98.3%, yield 98.0%.
Upper step product is put into 370ml methanol, dissolved clarification is stirred at room temperature, is gradually heated to 65 DEG C, back flow reaction 1 is small
When, HPLC monitors end of reaction, removes methanol under reduced pressure, is down to room temperature, and 200ml acetone is added, and stirs 1h, filtering, filtrate decompression
It is concentrated into original volume 1/3, is down to room temperature, 100ml petroleum ether is added, crystallisation by cooling obtains white solid 41g, i.e. 3- hydroxyl azepine
Cyclobutane hydrochloride, HPLC detect purity 98.5%, yield 91.5%.
Embodiment 4
N- benzyl -3- hydroxy azetidine 100g (0.42mol) is added in 2L reaction flask, toluene 1000ml is stirred molten
Clearly, -5 DEG C are cooled to, 108g chloroformate -1-chloro-ethyl ester (0.76mol) is dissolved in 80ml toluene, is slowly dripped in Xiang Shangshu solution
Add, control temperature is no more than 0 DEG C during being added dropwise, and thermotonus is continued to after being added dropwise 10 minutes, then slowly heated up
To 70 DEG C, continue to react 2 hours at this temperature, HPLC monitors end of reaction, and cooling, 45 DEG C are concentrated to dryness, and are produced
Product 72.4g, HPLC detect purity 98.0%, yield 96.5%.
Upper step product is put into 370ml methanol, dissolved clarification is stirred at room temperature, is gradually heated to 65 DEG C, back flow reaction 1 is small
When, HPLC monitors end of reaction, removes methanol under reduced pressure, is down to room temperature, and 200ml acetone is added, and stirs 1h, filtering, filtrate decompression
It is concentrated into original volume 1/3, is down to room temperature, 100ml petroleum ether is added, crystallisation by cooling obtains white solid 41.5g, i.e. 3- hydroxyl nitrogen
Azetidine hydrochloride, HPLC detect purity 98.3%, yield 92.6%.
This specific implementation is reacted using epoxychloropropane as raw material with benzylamine or diphenyl methylamine, and 1- benzyl -3- hydroxyl is generated
Azetidine or 1- benzhydryl -3- hydroxy azetidine, 1- benzyl -3- hydroxy azetidine or 1- benzhydryl -
Substitution reaction occurs for 3- hydroxy azetidine and chloroformate -1-chloro-ethyl ester, and intermediate product is separable to be come out or directly organic
It is heated in solvent, obtains final products 3- hydroxy azetidine hydrochloride.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (3)
1. a kind of N- aryl-heterocyclic butane takes off aryl method, which comprises the following steps:
Step 1: 1- benzyl -3- hydroxy azetidine or 1- benzhydryl -3- hydroxy azetidine are dissolved in organic molten
In agent, it is cooled to -10~0 DEG C；
Step 2: the chloroformate -1-chloro-ethyl ester of 1.1~2.1 equivalents is slowly added dropwise in step 1 acquired solution；
Step 3: step 2 acquired solution is heated to 50~80 DEG C, is reacted 1~3 hour, evaporating solvent under reduced pressure obtains first
Walk product；
Step 4: first step product is dissolved in 5 times of amount methanol, stirring and dissolving, is heated to 60~65 DEG C, back flow reaction at room temperature
1~2 hour；
Step 5: by step 4 acquired solution evaporating solvent under reduced pressure, being added acetone, stirs 1h, filtering；
Step 6: filtrate decompression obtained by step 5 is concentrated, and petroleum ether and stirring is added, and cooling crystallization obtains white solid, i.e. 3-
Hydroxy azetidine hydrochloride.
2. the method according to claim 1, wherein organic solvent described in step 1 be 1,2- dichloroethanes,
One of toluene, 1,4- dioxane.
3. the method according to claim 1, wherein the chlorine of 1.1~2.1 equivalents is slowly added dropwise described in step 2
Reaction temperature when formic acid -1- chloroethene ester is 0 DEG C or less.
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| CN201310298375.6A CN104292142B (en) | 2013-07-17 | 2013-07-17 | A kind of de- aryl method of N- aryl-heterocyclic butane |
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| CN1585772A (en) * | 2001-11-21 | 2005-02-23 | 千禧药品公司 | Chemokine receptor antagonists and methods of use thereof |
| US20060128685A1 (en) * | 2003-02-07 | 2006-06-15 | Daiichi Pharmaceutical Co., Ltd., | Pyrazole derivative |
| CN102656158A (en) * | 2009-11-18 | 2012-09-05 | Fab药物股份公司 | Novel heterocyclic acrylamides and their use as pharmaceuticals |
| CN102827052A (en) * | 2012-09-13 | 2012-12-19 | 甘肃科瑞生物科技有限公司 | Method for synthesizing 3-hydroxy-azetidinehydrochloride |
| WO2013014448A1 (en) * | 2011-07-27 | 2013-01-31 | Astrazeneca Ab | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
-
2013
- 2013-07-17 CN CN201310298375.6A patent/CN104292142B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1585772A (en) * | 2001-11-21 | 2005-02-23 | 千禧药品公司 | Chemokine receptor antagonists and methods of use thereof |
| US20060128685A1 (en) * | 2003-02-07 | 2006-06-15 | Daiichi Pharmaceutical Co., Ltd., | Pyrazole derivative |
| CN102656158A (en) * | 2009-11-18 | 2012-09-05 | Fab药物股份公司 | Novel heterocyclic acrylamides and their use as pharmaceuticals |
| WO2013014448A1 (en) * | 2011-07-27 | 2013-01-31 | Astrazeneca Ab | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN102827052A (en) * | 2012-09-13 | 2012-12-19 | 甘肃科瑞生物科技有限公司 | Method for synthesizing 3-hydroxy-azetidinehydrochloride |
Non-Patent Citations (1)
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| 合成1-(1，3-噻唑啉-2-基) -3-巯基氮杂环丁烷盐酸盐的工艺改进;王杰等;《合成化学》;20130630;第21卷(第3期);第367-369页 |
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