CN102617503A - Novel synthetic method of (S)-3-morpholinyl carboxylic acid - Google Patents
Novel synthetic method of (S)-3-morpholinyl carboxylic acid Download PDFInfo
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Abstract
The invention discloses a novel synthetic method of (S)-3-morpholinyl carboxylic acid, which comprises the following steps: (1) taking L-serine as a raw material to synthesize L-serine tert-butyl ester; (2) dissolving L-serine tert-butyl ester in dichloromethane, adding a dichloromethane solution of chloroacetyl chloride drop by drop to obtain N-chloroacetyl-L-serine tert-butyl ester; (3) dissolving N-chloroacetyl-L-serine tert-butyl ester in a toluene solution, adding the toluene solution of sodium ethoxide drop by drop to obtain (S)-5-oxo 3-morpholinyl carboxylic acid tert-butyl ester; (4) dissolving (S)-5-oxo 3-morpholinyl carboxylic acid tert-butyl ester in methanol, successively adding aluminum trichloride and sodium borohydride to carry out a reaction to obtain the (S)-3-morpholinyl carboxylic acid tert-butyl ester; (5) dissolving (S)-3-morpholinyl carboxylic acid tert-butyl ester in methanol, adding a methanol solution of hydrogen chloride for reacting to obtain the (S)-3-morpholinyl carboxylic acid. The method of the invention has the advantages of mild reaction condition, easily available raw material and less three waste, and is suitable for industrial production.
Description
Technical field
The present invention relates to the new synthetic method of a kind of medicine intermediate (S)-morpholinyl carboxylic acid, belong to that organic intermediate is synthetic, the synthetic field of medicine intermediate.
Background technology
(S)-and the morpholinyl carboxylic acid is a kind of broad-spectrum organic medicine intermediate, and existing synthetic technology exists expensive raw materials to be not easy to obtain usually, and cost is higher, severe reaction conditions, yield is lower, shortcomings such as the suitability for industrialized production that do not suit.
Aspect material choice; Prior art adopts hydroxyl raw material and the ketone that contains unsaturated double-bond under the condition of catalyzer, to react usually; The condition of follow-up acylation reaction and Guan Huan process is improved, need certain temperature, catalyzer is difficult for selecting; By product is more, and yield is also lower.
The L-Serine is a kind of white crystalline powder, can make the entire reaction mild condition as the raw material that synthesizes (S)-morpholinyl carboxylic acid, and yield is high.
Summary of the invention
For solving the problems of the technologies described above, the new synthetic method of the present invention provides a kind of (S)-morpholinyl carboxylic acid is a raw material with the L-Serine, and cost is lower, and reaction conditions is gentle, and the three wastes are few, suitable industrial production.
The present invention realizes through following technical scheme:
A kind of new synthetic method of (S)-morpholinyl carboxylic acid is to realize through following step:
(1) the L-Serine is dissolved in the tert.-butyl acetate, drips catalyzer at 0-10 ℃, intensification is stirred and is reacted, and reaction finishes after scouring, extraction, and drying gets the L-serine tert-butyl;
(2) the L-serine tert-butyl is dissolved in the methylene dichloride, the dichloromethane solution at 0-10 ℃ of dropping chloroacetyl chloride heats up, and stirs and reacts, and reaction finishes after scouring, and drying gets N-chloracetyl-L-serine tert-butyl;
(3) N-chloracetyl-L-serine tert-butyl is dissolved in the toluene solution, at 0-30 ℃ of toluene solution that drips sodium ethylate, heats up and react, reaction finishes the back shrend reaction of going out, washing, and drying gets (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester;
(4) (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester is dissolved in the methyl alcohol, adds aluminum chloride and Peng Qinghuana successively at-10-0 ℃, heat up and react, reaction is washed after finishing, drying, S-3-morpholinyl carboxylic acid tert-butyl ester;
(5) (S)-morpholinyl carboxylic acid tert-butyl ester is dissolved in the methyl alcohol,, heats up and react at-10-0 ℃ of methanol solution that drips hydrogenchloride, revolve after reaction finishes dried, (S)-morpholinyl carboxylic acid.
The L-Serine in the said step (1) and the mol ratio of tert.-butyl acetate are 1: (1-5), temperature of reaction is 10-60 ℃.
Catalyzer in the said step (1) is a perchloric acid solution, and concentration is 10-50%, and the mol ratio of add-on and said L-Serine is (0.05-0.5): 1.
The L-serine tert-butyl in the said step (2) and the mol ratio of chloroacetyl chloride are 1: (1-5), the addition of methylene dichloride is the every gram of a 2-30mL/ L-serine tert-butyl, and temperature of reaction is 10-40 ℃.
The N-chloracetyl-L-serine tert-butyl in the said step (3) and the mol ratio of sodium ethylate are 1: (1-4), the addition of toluene is the every gram of 2-30mL/ N-chloracetyl-L-serine tert-butyl, and temperature of reaction is 30-110 ℃.
(the S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester in the said step (4) and the mol ratio of Peng Qinghuana are 1: (0.5-3), the addition of methyl alcohol is the every gram of 5-30mL/ (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester, and temperature of reaction is 0-40 ℃.
Hydrogen chloride methanol solution concentration in the said step (5) is 30-35%, and the addition of hydrogen chloride methanol solution is the every gram of 2-20mL/ (S)-morpholinyl carboxylic acid tert-butyl ester, and the addition of methyl alcohol is the every gram of 5-30mL/ (S)-morpholinyl carboxylic acid tert-butyl ester.
Synthetic route of the present invention is following:
Specifically may be summarized to be: do initial feed with the L-Serine and synthesize (S)-morpholinyl carboxylic acid,
The 1st step was made catalyzer with perchloric acid, made protection reagent with tert.-butyl acetate, carried out the protection of L-Serine.
The 2nd step was done reaction reagent with chloroacetyl chloride, in methylene dichloride, carried out acylation reaction.
The 3rd step was done alkali with sodium ethylate, in toluene, closed ring.
The 4th step, under the catalysis of aluminum chloride, reducing carbonyl, Peng Qinghuana and aluminum chloride were the gentle original reagent of going back with Peng Qinghuana, selective height in this reaction, and reaction conditions is gentle, characteristics such as yield height.
The 5th step carried out acidifying with hydrogenchloride and gets final product.
Beneficial effect of the present invention is: reaction conditions is gentle, adopts ice-water bath and hot water bath can reach the temperature of reaction requirement, and the laboratory also can be operated; By product is few, reacts single-minded; Yield is high, and yield can reach more than 95%.
Embodiment
Below in conjunction with embodiment, the present invention is further specified.
Embodiment 1
The first step operation process
L-Serine 10.5g is dissolved in the tert.-butyl acetate of 20ml, and at 0 ℃ of 5ml aqueous solution that slowly drips 2g perchloric acid, reaction solution slowly is being warming up to room temperature; At room temperature stirred 10ml washing then, 10ml ammonium chloride washed 8 hours; Water merges, and uses salt of wormwood to transfer pH to be 9-10, uses the 100ml*3 dichloromethane extraction; Methylene dichloride is used anhydrous sodium sulfate drying, revolves driedly, obtains the faint yellow oily thing of 10.0g (65.0%) midbody 2 (L-serine tert-butyls).
The second step operation process
10g midbody 2 is dissolved in the 100ml methylene dichloride, and at 0 ℃ of 30ml dichloromethane solution that slowly drips 8.4g Mono Chloro Acetic Acid chlorine, reaction solution slowly is being warming up to room temperature; At room temperature stirred 1 hour, and added the sodium bicarbonate aqueous solution of 50ml (50%), layering; The washing of organic phase water 30ml salt; Anhydrous sodium sulfate drying revolves driedly, obtains 12.3g (83.7%) midbody 3 (N-chloracetyl-L-serine tert-butyl).
The three-step reaction operating process
10g midbody 3 is dissolved in the 50ml toluene, at room temperature slowly splashes in the toluene solution of 50ml of 6.8g sodium ethylate, after dropwising; Slowly be warming up to 60 ℃, be incubated 6 hours, cooling; Add the 50ml shrend reaction of going out, layering, toluene layer is washed; Drying is revolved driedly, obtains 8.1g (95.8%) midbody 4 (S-5-oxo-morpholinyl carboxylic acid tert-butyl ester).
The four-step reaction operating process
8g midbody 4 is dissolved in the 80ml methyl alcohol, slowly adds the 10g aluminum chloride, adition process meeting very exothermic at 0 ℃; 0 ℃ of insulated and stirred 1 hour adds the 1.5g Peng Qinghuana then in a small amount in batches, adds under the room temperature of back to stir 2 hours; The aqueous solution 100ml that adds saturated sodium carbonate is with methylene dichloride 100*3 extraction, anhydrous sodium sulfate drying; Revolve driedly, obtain 6.2g (83.8%) midbody 5 (S-3-morpholinyl carboxylic acid tert-butyl ester).
The 5th step operation process
6g midbody 5 is dissolved in the 40ml methyl alcohol, and at 0 ℃ of methanol solution of 30% that slowly adds 20ml hydrogenchloride, 0 ℃ was stirred 1 hour, stirred one hour under the room temperature, revolved driedly, obtained 5.2g (97.2%) the finished product S-3-morpholinyl carboxylic acid.
Embodiment 2
The first step operation process
L-Serine 10.5g is dissolved in the tert.-butyl acetate of 30ml, and at 0 ℃ of 5ml aqueous solution that slowly drips 4g perchloric acid, reaction solution slowly is being warming up between 20-40 ℃; Stirred 10 hours 15ml washing then, 15ml ammonium chloride washed down at 20-40 ℃; Water merges, and uses salt of wormwood to transfer pH to be 9-10, uses the 100ml*3 dichloromethane extraction; Methylene dichloride is used anhydrous sodium sulfate drying, revolves driedly, obtains the faint yellow oily thing of 10.0g (65.0%) midbody 2 (L-serine tert-butyls).
The second step operation process
10g midbody 2 is dissolved in the 100ml methylene dichloride, and at 10 ℃ of 50ml dichloromethane solutions that slowly drip 13.5g Mono Chloro Acetic Acid chlorine, reaction solution slowly is being warming up to 20-30 ℃; Between 20-30 ℃, stirred 1 hour down, add the sodium bicarbonate aqueous solution of 50ml (50%), layering; The washing of organic phase water 30ml salt; Anhydrous sodium sulfate drying revolves driedly, obtains 13.2g (85.6%) midbody 3 (N-chloracetyl-L-serine tert-butyl).
The three-step reaction operating process
10g midbody 3 is dissolved in the 50ml toluene, at room temperature slowly splashes in the toluene solution of 50ml of 5.5g sodium ethylate, after dropwising; Slowly be warming up to 80-10 ℃, be incubated 6 hours, cooling; Add the 50ml shrend reaction of going out, layering, toluene layer is washed; Drying is revolved driedly, obtains 8.5g (96.1%) midbody 4 (S-5-oxo-morpholinyl carboxylic acid tert-butyl ester).
The four-step reaction operating process
8g midbody 4 is dissolved in the 80ml methyl alcohol, slowly adds the 8g aluminum chloride, adition process meeting very exothermic at 0 ℃; 0 ℃ of insulated and stirred 1 hour adds the 2.2g Peng Qinghuana then in a small amount in batches, is warming up to 20-40 ℃ after adding; Stirred 2 hours, and added the aqueous solution 100ml of saturated sodium carbonate, extract with methylene dichloride 100*3; Anhydrous sodium sulfate drying revolves driedly, obtains 6.5g (84.2%) midbody 5 (S-3-morpholinyl carboxylic acid tert-butyl ester).
The 5th step operation process
6g midbody 5 is dissolved in the 40ml methyl alcohol, and at-10 ℃ of methanol solutions of 30% that slowly add the 20ml hydrogenchloride ,-10 ℃ were stirred 1 hour, were warming up to 20-30 ℃, stirred one hour, revolved driedly, obtained 5.8g (98.5%) the finished product S-3-morpholinyl carboxylic acid.
Embodiment 3
The first step operation process
L-Serine 10.5g is dissolved in the tert.-butyl acetate of 20ml, and at 5 ℃ of 5ml aqueous solution that slowly drip 3g perchloric acid, reaction solution slowly is being warming up to 50-60 ℃; Stirred 8 hours 10ml washing then, 10ml ammonium chloride washed down at 50-60 ℃; Water merges, and uses salt of wormwood to transfer pH to be 9-10, uses the 100ml*3 dichloromethane extraction; Methylene dichloride is used anhydrous sodium sulfate drying, revolves driedly, obtains the faint yellow oily thing of 10.0g (65.0%) midbody 2 (L-serine tert-butyls).
The second step operation process
10g midbody 2 is dissolved in the 100ml methylene dichloride, and at 0 ℃ of 30ml dichloromethane solution that slowly drips 10g Mono Chloro Acetic Acid chlorine, reaction solution slowly is being warming up to 30-40 ℃; Stirred 1 hour down at 30-40 ℃, add the sodium bicarbonate aqueous solution of 50ml (50%), layering; The washing of organic phase water 30ml salt; Anhydrous sodium sulfate drying revolves driedly, obtains 11.5g (82.5%) midbody 3 (N-chloracetyl-L-serine tert-butyl).
The three-step reaction operating process
10g midbody 3 is dissolved in the 50ml toluene, at room temperature slowly splashes in the toluene solution of 50ml of 9.5g sodium ethylate, after dropwising; Slowly be warming up to 80-100 ℃, be incubated 6 hours, cooling; Add the 50ml shrend reaction of going out, layering, toluene layer is washed; Drying is revolved driedly, obtains 8.1g (93.6%) midbody 4 (S-5-oxo-morpholinyl carboxylic acid tert-butyl ester).
The four-step reaction operating process
8g midbody 4 is dissolved in the 80ml methyl alcohol, slowly adds the 8.5g aluminum chloride, adition process meeting very exothermic at-5 ℃;-5 ℃ of insulated and stirred 1 hour add the 1.2g Peng Qinghuana then in a small amount in batches, add under the room temperature of back to stir 2 hours; The aqueous solution 100ml that adds saturated sodium carbonate is with methylene dichloride 100*3 extraction, anhydrous sodium sulfate drying; Revolve driedly, obtain 6.0g (82.9%) midbody 5 (S-3-morpholinyl carboxylic acid tert-butyl ester).
The 5th step operation process
6g midbody 5 is dissolved in the 40ml methyl alcohol, and at-5 ℃ of methanol solutions of 30% that slowly add the 30ml hydrogenchloride ,-5 ℃ were stirred 1 hour, stirred one hour under the room temperature, revolved driedly, obtained 4.9g (95.0%) the finished product S-3-morpholinyl carboxylic acid.
Claims (7)
1. the new synthetic method of (S)-morpholinyl carboxylic acid is characterized in that being realizing through following step:
(1) the L-Serine is dissolved in the tert.-butyl acetate, drips catalyzer at 0-10 ℃, intensification is stirred and is reacted, and reaction finishes after scouring, extraction, and drying gets the L-serine tert-butyl;
(2) the L-serine tert-butyl is dissolved in the methylene dichloride, the dichloromethane solution at 0-10 ℃ of dropping chloroacetyl chloride heats up, and stirs and reacts, and reaction finishes after scouring, and drying gets N-chloracetyl-L-serine tert-butyl;
(3) N-chloracetyl-L-serine tert-butyl is dissolved in the toluene solution, at 0-30 ℃ of toluene solution that drips sodium ethylate, heats up and react, reaction finishes the back shrend reaction of going out, washing, and drying gets (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester;
(4) (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester is dissolved in the methyl alcohol, adds aluminum chloride and Peng Qinghuana successively at-10-0 ℃, heat up and react, reaction is washed after finishing, drying, (S)-morpholinyl carboxylic acid tert-butyl ester;
(5) (S)-morpholinyl carboxylic acid tert-butyl ester is dissolved in the methyl alcohol,, heats up and react at-10-0 ℃ of methanol solution that drips hydrogenchloride, revolve after reaction finishes dried, (S)-morpholinyl carboxylic acid.
2. the new synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1, it is characterized in that L-Serine and the mol ratio of tert.-butyl acetate in the said step (1) is 1: (1-5), temperature of reaction is 10-60 ℃.
3. the new synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1 is characterized in that the catalyzer in the said step (1) is a perchloric acid solution, and concentration is 10-50%, and the mol ratio of add-on and said L-Serine is (0.05-0.5): 1.
4. the new synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1; It is characterized in that L-serine tert-butyl and the mol ratio of chloroacetyl chloride in the said step (2) are 1: (1-5); The addition of methylene dichloride is the every gram of a 2-30mL/ L-serine tert-butyl, and temperature of reaction is 10-40 ℃.
5. the new synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1; It is characterized in that N-chloracetyl-L-serine tert-butyl and the mol ratio of sodium ethylate in the said step (3) are 1: (1-4); The addition of toluene is the every gram of 2-30mL/ N-chloracetyl-L-serine tert-butyl, and temperature of reaction is 30-110 ℃.
6. the new synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1; It is characterized in that S-5-oxo-morpholinyl carboxylic acid tert-butyl ester and the mol ratio of Peng Qinghuana in the said step (4) are 1: (0.5-3); The addition of methyl alcohol is the every gram of 5-30mL/ S-5-oxo-morpholinyl carboxylic acid tert-butyl ester, and temperature of reaction is 0-40 ℃.
7. the new synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1; It is characterized in that the hydrogen chloride methanol solution concentration in the said step (5) is 30-35%; The addition of hydrogen chloride methanol solution is the every gram of 2-20mL/ (S)-morpholinyl carboxylic acid tert-butyl ester, and the addition of methyl alcohol is the every gram of 5-30mL/ (S)-morpholinyl carboxylic acid tert-butyl ester.
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Cited By (3)
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| CN103232369A (en) * | 2013-05-09 | 2013-08-07 | 成都郑源生化科技有限公司 | Preparation method of fmoc chloride glutamic acid-5-tert-butyl ester |
| CN103880768A (en) * | 2014-02-26 | 2014-06-25 | 南通大学 | Chemical synthesis method of 3-cyclobutylmorpholine |
| CN103880770A (en) * | 2014-03-18 | 2014-06-25 | 南通佰华生物医药研究有限公司 | Method for preparing chiral 3-morpholine methanol and 3-morpholine formic acid compounds |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232369A (en) * | 2013-05-09 | 2013-08-07 | 成都郑源生化科技有限公司 | Preparation method of fmoc chloride glutamic acid-5-tert-butyl ester |
| CN103232369B (en) * | 2013-05-09 | 2015-07-01 | 成都郑源生化科技有限公司 | Preparation method of fmoc chloride glutamic acid-5-tert-butyl ester |
| CN103880768A (en) * | 2014-02-26 | 2014-06-25 | 南通大学 | Chemical synthesis method of 3-cyclobutylmorpholine |
| CN103880768B (en) * | 2014-02-26 | 2016-04-13 | 南通大学 | A kind of chemical synthesis process of 3-cyclobutyl morpholine |
| CN103880770A (en) * | 2014-03-18 | 2014-06-25 | 南通佰华生物医药研究有限公司 | Method for preparing chiral 3-morpholine methanol and 3-morpholine formic acid compounds |
| CN103880770B (en) * | 2014-03-18 | 2017-08-08 | 南通佰华生物医药研究有限公司 | The preparation method of chiral 3 morpholine methanol classes and 3 morpholine formic acid compounds |
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