CN1986547A - Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron - Google Patents
Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron Download PDFInfo
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- CN1986547A CN1986547A CN 200510111852 CN200510111852A CN1986547A CN 1986547 A CN1986547 A CN 1986547A CN 200510111852 CN200510111852 CN 200510111852 CN 200510111852 A CN200510111852 A CN 200510111852A CN 1986547 A CN1986547 A CN 1986547A
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Abstract
The present invention relates to industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane in one kettle. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.
Description
Technical field:
The present invention relates to a kind of 5-azepine-2-oxa--3-ketone-dicyclo-[2 of N-protected; 2,1] preparation method of iieptanes pharmaceutical intermediate, particularly a kind of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2,1] heptane one kettle way synthetic industrialized process for preparing.
Background technology:
The 5-azepine of N-protected-2-oxa--3-ketone-dicyclo-[2,2,1] heptane is the pharmaceutical intermediate of outbalance, but does not up to the present effectively prepare the industrial preparative method of this product.Once two kinds of preparation methods had been reported in the document, method one, with the L-oxyproline is raw material, at first through blocking group protection commonly used, obtain the 5-azepine-2-oxa--3-ketone-dicyclo-[2 of N-protected then by the Mitsunobu reaction, 2,1] (Heterocycles 1983,817-828) for heptane; Method two; the same L-of protection earlier oxyproline; using Jone ' s reagent oxidation secondary alcohol then is ketone; use sodium borohydride to obtain reduzate cis hydroxyl groups proline(Pro) afterwards; use dicyclohexylcarbodiimide (DCC) condensation to obtain the 5-azepine-2-oxa--3-ketone-dicyclo-[2 of N-protected at last; 2,1] heptane (Aust.J.Chem.1967,1493).
Document synthetic route 1:
Said synthesis route 1 is not suitable for the technical scale batch reaction, this be because:
(a) the raw material that uses expensive, the cost height for example, must be used diethyl azodiformate (DEAD) and triphenylphosphine and carry out Mitsunobu and react;
(b) reaction can generate more by product, causes the aftertreatment technology complexity, needs the last product of column chromatography purification, and resulting product yield and product purity can not be satisfactory for plant-scale preparation method.
Document synthetic route 2:
Said synthesis route 2 is not suitable for the technical scale batch reaction, this be because:
(a) using Jone ' s reagent oxidation secondary alcohol is ketone, and the requirement of protecting group is wanted high relatively: Jone ' s reagent (sulphuric acid soln of chromium trioxide) is highly acid, and so claimed base must be acidproof, has significant limitation like this for reaction;
(b) the by product environmental pollution of chromium trioxide is serious;
(c) the raw material that uses expensive, the cost height for example, is used dicyclohexylcarbodiimide (DCC) at last,
(d) by product that generates of reaction difficulty remove, also need the column chromatography purification product, yield has only 50～60%, can't realize the industrial production of mass-producing.
Summary of the invention:
The technical issues that need to address of the present invention are: simplify the technological operation flow process; Shorten the production time; Save production cost; A kind of N-tertbutyloxycarbonyl that is produced on a large scale-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane one kettle way synthetic industrialized process for preparing is provided.
Technical scheme of the present invention:
The present invention is a raw material with L-oxyproline conventional, that be easy to get; by obtaining N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2 behind esterification, tertbutyloxycarbonyl protection and tosic acid esterification one kettle way and the hydrolysis and the one kettle way that lactonizes; 2,1] heptane.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we at first carry out esterification reaction of organic acid, adopt one kettle way to carry out tertbutyloxycarbonyl protection and tosic acid esterification then.
Esterification reaction of organic acid, methyl alcohol is made reaction solvent, and reaction reagent is selected from a kind of in sulfur oxychloride, the vitriol oil and the Acetyl Chloride 98Min., and temperature of reaction is 0 ℃-60 ℃, and optimal reaction temperature is room temperature (20 ℃-25 ℃); Reacted crude product carries out tertbutyloxycarbonyl protection and tosic acid esterification reaction with one kettle way; reaction reagent BOC acid anhydrides and Tosyl chloride; reaction solvent is selected tetrahydrofuran (THF), 1 for use; a kind of in 4-dioxane and the methylene dichloride; pyridine is made alkali; temperature of reaction is 0 ℃-30 ℃, and optimal reaction temperature is room temperature (20 ℃-25 ℃), three step yields 83～89%.
Then, we are hydrolyzed with one kettle way and react and lactonization reaction, select alkali commonly used and that be easy to get for use, as sodium hydroxide and potassium hydroxide, reaction solvent is selected acetone commonly used for use, temperature of reaction be room temperature to reflux temperature (69 ℃), preferable reaction temperature is reflux temperature (69 ℃).The two-step reaction yield is 84～86%.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally, and having solved among existing N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane preparation technology needs column chromatography purification, problem that can't large-scale production; Provide that a kind of whole yield is higher, operating process among the one kettle way preparation technology that simplifies; Shortened the production time; Save production cost; And intermediate can be purified by recrystallization, therefore can carry out large-scale industrial production.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
L-oxyproline (300g, 2.29mol) be dissolved in anhydrous methanol (2.0L), dripping thionyl chloride (335g under the room temperature, 2.8mol), reaction solution reflux to stir 1 hour, directly was concentrated into driedly, added tetrahydrofuran (THF) (6.0L) then under the room temperature, pyridine (727g, 9.2mol) and BOC acid anhydrides (520g, 2.4mol), react after 1 hour, add Tosyl chloride (437g, 2.3mol), continue reaction 2 hours under the room temperature, add saturated sodium bicarbonate aqueous solution (6L), layering, water uses ethyl acetate (3L) to extract again, merge organic phase, be concentrated into dried crude product, behind methyl tertiary butyl ether (2.5L) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (813g, 2.04mol), productive rate: 89%.
1H?NMR(400MHz，DMSO-d
6)：δ7.80(d，J＝8.0Hz，2H)，7.48(d，J＝8.0Hz，2H)，5.04(s，1H)，4.18(m，1H)，3.62(d，J＝9.2Hz，3H)，3.35～3.45(m，2H)，3.40(s，2H)，2.05～2.40(m，2H)，1.30(d，J＝9.2Hz，9H)；Ms(M
++1，400.1)。
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
(852g 2.14mol) is dissolved in acetone (6.0L) to N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester, adds sodium hydroxide (170g under the room temperature, 4.3mol), refluxed about 69 ℃ of reflux temperature, cool to room temperature 2 hours, add elutriation and go out solid, filter thick product, the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (381g, 1.8mol). productive rate: 84%.
1H?NMR(400MHz，CDCl
3)：δ5.05(s，1H)，4.5(s，1H)，3.40～3.55(m，2H)，2.00～2.20(m，2H)，1.45(s，9H)；Ms(M
++1，214.1)。
Embodiment 2
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
L-oxyproline (60g, 0.46mol) be dissolved in anhydrous methanol (0.4L), drip sulfuric acid (55g under the room temperature, 0.56mol), reaction solution refluxes and stirred 1 hour, concentrate as for, add under the room temperature then and be dissolved in methylene dichloride (1.2L), (108g is 1.4mol) with BOC acid anhydrides (104g to add pyridine, 0.48mol), react after 1 hour, and the adding Tosyl chloride (88g, 0.46mol), continue reaction 2 hours, add saturated sodium bicarbonate aqueous solution (1L), layering, organic phase water (1L) washing again, be concentrated into dried crude product, behind methyl tertiary butyl ether (0.6L) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (152g, 0.38mol), productive rate: 83%.Its test data is shown in above-mentioned example 1.
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
(1136g 2.85mol) is dissolved in acetone (8L) to N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester, adds potassium hydroxide (318g under the room temperature, 5.7mol), refluxed about 69 ℃ of reflux temperature, cool to room temperature 2 hours, add elutriation and go out solid, filter thick product, the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (522g, 2.45mol). productive rate: 86%.Its test data is shown in above-mentioned example 1.
Embodiment 3
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
L-oxyproline (3g, 22.9mmol) be dissolved in anhydrous methanol (20mL), dripping acetyl chloride (2.2g under the room temperature, 28mmol), reaction solution reflux to stir 1 hour, was concentrated into driedly, added 1 under the room temperature then, 4-dioxane (60mL), add pyridine (g under the room temperature, 63mmol) (5.2g 24mmol), reacts after 1 hour with the BOC acid anhydrides, add Tosyl chloride (4.4g, 23mmol), continue reaction 2 hours, add saturated sodium bicarbonate aqueous solution (30mL), layering, organic phase water (30mL) washing again is concentrated into dried crude product, behind methyl tertiary butyl ether (25mL) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (8.0g, 20.0mmol), productive rate: 87%.Its test data is shown in above-mentioned embodiment 1.
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
Prepare corresponding product according to the second described one kettle way hydrolysis of step and lactonization reaction processing condition and operation steps in the foregoing description 1, its test data is shown in above-mentioned example 1.
Claims (9)
1, N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] industrialized process for preparing of heptane one kettle way; it is characterized in that; with the L-oxyproline is raw material; by obtaining N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane behind esterification, tertbutyloxycarbonyl protection and tosic acid esterification one kettle way and the hydrolysis and the one kettle way that lactonizes.
2, the industrialized process for preparing of N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane one kettle way is characterized in that the reaction formula of above-mentioned reaction is:
3, N-tertbutyloxycarbonyl according to claim 1 and 2-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] industrialized process for preparing of heptane one kettle way; it is characterized in that; carry out in esterification, tertbutyloxycarbonyl protection and the tosic acid esterification at one kettle way; the reaction solvent of the first step esterification is a methyl alcohol, and reaction reagent is selected from a kind of in sulfur oxychloride, the vitriol oil and the Acetyl Chloride 98Min..
4, the industrialized process for preparing of N-tertbutyloxycarbonyl according to claim 3-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane one kettle way is characterized in that, temperature of reaction is 0 ℃-60 ℃.
5, the industrialized process for preparing of N-tertbutyloxycarbonyl according to claim 4-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane one kettle way is characterized in that temperature of reaction is a room temperature.
6, N-tertbutyloxycarbonyl according to claim 1 and 2-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] industrialized process for preparing of heptane one kettle way; it is characterized in that one kettle way carries out tertbutyloxycarbonyl protection and tosic acid esterification reaction, reaction reagent BOC acid anhydrides and Tosyl chloride; reaction solvent is selected from tetrahydrofuran (THF), 1; a kind of in 4-dioxane and the methylene dichloride, pyridine is made alkali, and temperature of reaction is 0 ℃-30 ℃.
7, the industrialized process for preparing of N-tertbutyloxycarbonyl according to claim 6-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane one kettle way is characterized in that temperature of reaction is a room temperature.
8, N-tertbutyloxycarbonyl according to claim 1 and 2-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] industrialized process for preparing of heptane one kettle way, it is characterized in that, one kettle way is hydrolyzed in reaction and the lactonization reaction, used alkali is selected from sodium hydroxide and potassium hydroxide, and reaction solvent is an acetone, and temperature of reaction is that room temperature is to 69 ℃ of reflux temperatures.
9, the industrialized process for preparing of N-tertbutyloxycarbonyl according to claim 8-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane one kettle way is characterized in that, temperature of reaction is 69 ℃ of reflux temperatures.
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| CN200510111852A CN1986547B (en) | 2005-12-22 | 2005-12-22 | Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron |
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| CN104326960A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-proline |
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| JP2005220079A (en) * | 2004-02-05 | 2005-08-18 | Shionogi & Co Ltd | Synthesis of pyrrolidine compound and crystal therefor |
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Assignee: Hequan Pharmaceutical Co., Ltd., Shanghai Assignor: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Contract record no.: 2011310000059 Denomination of invention: Fixed zymological method for production of prostaglandin E* Granted publication date: 20100526 License type: Exclusive License Open date: 20070627 Record date: 20110509 |
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