CN102617503B - 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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- CN102617503B CN102617503B CN201110051128.7A CN201110051128A CN102617503B CN 102617503 B CN102617503 B CN 102617503B CN 201110051128 A CN201110051128 A CN 201110051128A CN 102617503 B CN102617503 B CN 102617503B
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Abstract
The invention discloses a 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 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)-morpholinyl carboxylic acid is a kind of broad-spectrum organic medicine intermediate, and existing synthetic technology exists raw material costliness to be not easy to obtain conventionally, and cost is higher, severe reaction conditions, and yield is lower, is not suitable for the shortcomings such as suitability for industrialized production.
Aspect material choice; the ketone that prior art conventionally adopts hydroxyl raw material and contains unsaturated double-bond reacts under the condition of catalyzer; make like this condition of follow-up acylation reaction and Guan Huan process improve; need certain temperature; catalyzer is difficult for selecting; by product is more, and yield is also lower.
Serine is a kind of white crystalline powder, as the raw material of synthetic (S)-morpholinyl carboxylic acid, can make whole reaction conditions gentleness, and yield is high.
summary of the invention
For solving the problems of the technologies described above, the invention provides the synthetic method of one (S)-morpholinyl carboxylic acid, take Serine as raw material, cost is lower, reaction conditions gentleness, the three wastes are few, suitable industrial production.
The present invention realizes by following technical scheme:
A kind of synthetic method of (S)-morpholinyl carboxylic acid is to realize by following step:
(1) Serine is dissolved in tert.-butyl acetate, at 0-10 ℃, drips catalyzer, heat up, stir and react, reaction finishes rear washing, and extraction is dry, obtains the Serine tert-butyl ester;
(2) the Serine tert-butyl ester is dissolved in methylene dichloride, at the dichloromethane solution of 0-10 ℃ of dropping chloroacetyl chloride, heats up, stir and react, reaction finishes rear washing, dry, obtains N-chloracetyl-Serine tert-butyl ester;
(3) N-chloracetyl-Serine tert-butyl ester is dissolved in toluene solution, at the toluene solution of 0-30 ℃ of dropping sodium ethylate, heats up and react, reaction finishes the rear shrend reaction of going out, washing, dry, obtain (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester;
(4) (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester is dissolved in methyl alcohol, at-10-0 ℃, adds successively aluminum chloride and sodium borohydride, heat up and react, after reaction finishes, wash, dry, obtain S-3-morpholinyl carboxylic acid tert-butyl ester;
(5) (S)-morpholinyl carboxylic acid tert-butyl ester is dissolved in methyl alcohol, at-10-0 ℃ of methanol solution that drips hydrogenchloride, heats up and react, after reaction finishes, be spin-dried for, (S)-morpholinyl carboxylic acid.
Serine in described step (1) and the mol ratio of tert.-butyl acetate are 1: (1-5), temperature of reaction is 10-60 ℃.
Catalyzer in described step (1) is perchloric acid solution, and concentration is 10-50%, and the mol ratio of add-on and described Serine is (0.05-0.5): 1.
The Serine tert-butyl ester in described step (2) and the mol ratio of chloroacetyl chloride are 1: (1-5), the addition of methylene dichloride is every gram of Serine tert-butyl ester of 2-30mL/, and temperature of reaction is 10-40 ℃.
N-chloracetyl-Serine tert-butyl ester in described step (3) and the mol ratio of sodium ethylate are 1: (1-4), the addition of toluene is every gram of N-chloracetyl-Serine tert-butyl ester of 2-30mL/, and temperature of reaction is 30-110 ℃.
(S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester in described step (4) and the mol ratio of sodium borohydride are 1: (0.5-3), the addition of methyl alcohol is 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 described step (5) is 30-35%, the addition of hydrogen chloride methanol solution is every gram of 2-20mL/ (S)-morpholinyl carboxylic acid tert-butyl ester, and the addition of methyl alcohol is every gram of 5-30mL/ (S)-morpholinyl carboxylic acid tert-butyl ester.
Synthetic route of the present invention is as follows:
Specifically may be summarized to be: with Serine, do initial feed and synthesize (S)-morpholinyl carboxylic acid,
The 1st step is made catalyzer with perchloric acid, makees protection reagent with tert.-butyl acetate, carries out the protection of Serine.
The 2nd step is done reaction reagent with chloroacetyl chloride, carries out acylation reaction in methylene dichloride.
The 3rd step is done alkali with sodium ethylate, closes ring in toluene.
The 4th step uses sodium borohydride under the catalysis of aluminum chloride, reducing carbonyl, and sodium borohydride and aluminum chloride are the gentle original reagent of going back, selective height in this reaction, reaction conditions gentleness, yield high.
The 5th step is carried out acidifying with hydrogenchloride and is obtained final product.
Beneficial effect of the present invention is: reaction conditions gentleness, and adopt ice-water bath and hot water bath can reach temperature of reaction requirement, laboratory also can operate; 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 will be further described.
Embodiment 1
The first step operation process
Serine 10.5g is dissolved in the tert.-butyl acetate of 20ml, at 0 ℃ of slow 5ml aqueous solution that drips 2g perchloric acid, reaction solution is slowly being warming up to room temperature, at room temperature stirs 8 hours, then 10ml washing, 10ml ammonium chloride washed, water merges, and with salt of wormwood, adjusting pH is 9-10, use 100ml*3 dichloromethane extraction, methylene dichloride anhydrous sodium sulfate drying, is spin-dried for, and obtains the faint yellow oily matter intermediate 2 of 10.0g (65.0%) (the Serine tert-butyl ester).
Second step operation process
10g intermediate 2 is dissolved in 100ml methylene dichloride; at 0 ℃ of slow 30ml dichloromethane solution that drips 8.4g Mono Chloro Acetic Acid chlorine; reaction solution is slowly being warming up to room temperature; at room temperature stir 1 hour, add the sodium bicarbonate aqueous solution of 50ml (50%), layering; the washing of organic phase water 30ml salt; anhydrous sodium sulfate drying, is spin-dried for, and obtains 12.3g (83.7%) intermediate 3 (N-chloracetyl-Serine tert-butyl ester).
Three-step reaction operating process
10g intermediate 3 is dissolved in 50ml toluene, at room temperature slowly splash in the toluene solution of 50ml of 6.8g sodium ethylate, after dropwising, be slowly warming up to 60 ℃, be incubated 6 hours, cooling, adds the 50ml shrend reaction of going out, layering, toluene layer washing, dry, be spin-dried for, obtain 8.1g (95.8%) intermediate 4 (S-5-oxo-morpholinyl carboxylic acid tert-butyl ester).
Four-step reaction operating process
8g intermediate 4 is dissolved in 80ml methyl alcohol, at 0 ℃, slowly add 10g aluminum chloride, adition process can very exothermic, and 0 ℃ of insulated and stirred 1 hour then adds 1.5g sodium borohydride in a small amount in batches, add under rear room temperature and stir 2 hours, add the aqueous solution 100ml of saturated sodium carbonate, with methylene dichloride 100*3 extraction, anhydrous sodium sulfate drying, be spin-dried for, obtain 6.2g (83.8%) intermediate 5 (S-3-morpholinyl carboxylic acid tert-butyl ester).
The 5th step operation process
6g intermediate 5 is dissolved in 40ml methyl alcohol, and at 0 ℃ of methanol solution of 30% that slowly adds 20ml hydrogenchloride, 0 ℃ is stirred 1 hour, stirs one hour under room temperature, is spin-dried for, and obtains 5.2g (97.2%) the finished product S-3-morpholinyl carboxylic acid.
Embodiment 2
The first step operation process
Serine 10.5g is dissolved in the tert.-butyl acetate of 30ml, at 0 ℃ of slow 5ml aqueous solution that drips 4g perchloric acid, reaction solution is slowly being warming up between 20-40 ℃, at 20-40 ℃, stir 10 hours, then 15ml washing, 15ml ammonium chloride washed, water merges, with salt of wormwood, adjusting pH is 9-10, use 100ml*3 dichloromethane extraction, methylene dichloride anhydrous sodium sulfate drying, is spin-dried for, and obtains the faint yellow oily matter intermediate 2 of 10.0g (65.0%) (the Serine tert-butyl ester).
Second step operation process
10g intermediate 2 is dissolved in 100ml methylene dichloride; at 10 ℃ of slow 50ml dichloromethane solutions that drip 13.5g Mono Chloro Acetic Acid chlorine; reaction solution is slowly being warming up to 20-30 ℃; between 20-30 ℃, lower stirring 1 hour, adds the sodium bicarbonate aqueous solution of 50ml (50%), layering; the washing of organic phase water 30ml salt; anhydrous sodium sulfate drying, is spin-dried for, and obtains 13.2g (85.6%) intermediate 3 (N-chloracetyl-Serine tert-butyl ester).
Three-step reaction operating process
10g intermediate 3 is dissolved in 50ml toluene, at room temperature slowly splash in the toluene solution of 50ml of 5.5g sodium ethylate, after dropwising, be slowly warming up to 80-10 ℃, be incubated 6 hours, cooling, adds the 50ml shrend reaction of going out, layering, toluene layer washing, dry, be spin-dried for, obtain 8.5g (96.1%) intermediate 4 (S-5-oxo-morpholinyl carboxylic acid tert-butyl ester).
Four-step reaction operating process
8g intermediate 4 is dissolved in 80ml methyl alcohol, at 0 ℃, slowly add 8g aluminum chloride, adition process can very exothermic, 0 ℃ of insulated and stirred 1 hour, then add in a small amount 2.2g sodium borohydride in batches, after adding, be warming up to 20-40 ℃, stir 2 hours, add the aqueous solution 100ml of saturated sodium carbonate, extract with methylene dichloride 100*3, anhydrous sodium sulfate drying, is spin-dried for, and obtains 6.5g (84.2%) intermediate 5 (S-3-morpholinyl carboxylic acid tert-butyl ester).
The 5th step operation process
6g intermediate 5 is dissolved in 40ml methyl alcohol, and at-10 ℃ of methanol solutions of 30% that slowly add 20ml hydrogenchloride ,-10 ℃ are stirred 1 hour, be warming up to 20-30 ℃, stir one hour, be spin-dried for, obtain 5.8g (98.5%) the finished product S-3-morpholinyl carboxylic acid.
Embodiment 3
The first step operation process
Serine 10.5g is dissolved in the tert.-butyl acetate of 20ml, at 5 ℃ of slow 5ml aqueous solution that drip 3g perchloric acid, reaction solution is slowly being warming up to 50-60 ℃, stirs 8 hours at 50-60 ℃, then 10ml washing, 10ml ammonium chloride washed, water merges, and with salt of wormwood, adjusting pH is 9-10, use 100ml*3 dichloromethane extraction, methylene dichloride anhydrous sodium sulfate drying, is spin-dried for, and obtains the faint yellow oily matter intermediate 2 of 10.0g (65.0%) (the Serine tert-butyl ester).
Second step operation process
10g intermediate 2 is dissolved in 100ml methylene dichloride; at 0 ℃ of slow 30ml dichloromethane solution that drips 10g Mono Chloro Acetic Acid chlorine; reaction solution is slowly being warming up to 30-40 ℃; at 30-40 ℃, stir 1 hour, add the sodium bicarbonate aqueous solution of 50ml (50%), layering; the washing of organic phase water 30ml salt; anhydrous sodium sulfate drying, is spin-dried for, and obtains 11.5g (82.5%) intermediate 3 (N-chloracetyl-Serine tert-butyl ester).
Three-step reaction operating process
10g intermediate 3 is dissolved in 50ml toluene, at room temperature slowly splash in the toluene solution of 50ml of 9.5g sodium ethylate, after dropwising, be slowly warming up to 80-100 ℃, be incubated 6 hours, cooling, adds the 50ml shrend reaction of going out, layering, toluene layer washing, dry, be spin-dried for, obtain 8.1g (93.6%) intermediate 4 (S-5-oxo-morpholinyl carboxylic acid tert-butyl ester).
Four-step reaction operating process
8g intermediate 4 is dissolved in 80ml methyl alcohol, at-5 ℃, slowly add 8.5g aluminum chloride, adition process can very exothermic, and-5 ℃ of insulated and stirred 1 hour then add 1.2g sodium borohydride in a small amount in batches, add under rear room temperature and stir 2 hours, add the aqueous solution 100ml of saturated sodium carbonate, with methylene dichloride 100*3 extraction, anhydrous sodium sulfate drying, be spin-dried for, obtain 6.0g (82.9%) intermediate 5 (S-3-morpholinyl carboxylic acid tert-butyl ester).
The 5th step operation process
6g intermediate 5 is dissolved in 40ml methyl alcohol, and at-5 ℃ of methanol solutions of 30% that slowly add 30ml hydrogenchloride ,-5 ℃ are stirred 1 hour, stir one hour under room temperature, are spin-dried for, and obtain 4.9g (95.0%) the finished product S-3-morpholinyl carboxylic acid.
Claims (6)
1. a synthetic method for (S)-morpholinyl carboxylic acid, it is characterized in that realizing by following step:
(1) Serine is dissolved in tert.-butyl acetate, at 0-10 ℃, drips catalyzer, heat up, stir and react, reaction finishes rear washing, and extraction is dry, obtains the Serine tert-butyl ester;
(2) the Serine tert-butyl ester is dissolved in methylene dichloride, at the dichloromethane solution of 0-10 ℃ of dropping chloroacetyl chloride, heats up, stir and react, reaction finishes rear washing, dry, obtains N-chloracetyl-Serine tert-butyl ester;
(3) N-chloracetyl-Serine tert-butyl ester is dissolved in toluene solution, at the toluene solution of 0-30 ℃ of dropping sodium ethylate, heats up and react, reaction finishes the rear shrend reaction of going out, washing, dry, obtain (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester;
(4) (S)-5-oxo-morpholinyl carboxylic acid tert-butyl ester is dissolved in methyl alcohol, at-10-0 ℃, add successively aluminum chloride and sodium borohydride, heat up and react, after reaction finishes, wash, dry, obtain (S)-morpholinyl carboxylic acid tert-butyl ester;
(5) (S)-morpholinyl carboxylic acid tert-butyl ester is dissolved in methyl alcohol, at-10-0 ℃ of methanol solution that drips hydrogenchloride, heats up and react, after reaction finishes, be spin-dried for, (S)-morpholinyl carboxylic acid,
Wherein, in described step (2), the mol ratio of the Serine tert-butyl ester and chloroacetyl chloride is 1: (1-5), the addition of methylene dichloride is every gram of Serine tert-butyl ester of 2-30mL/, and temperature of reaction is 10-40 ℃.
2. the synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1, is characterized in that Serine in described step (1) and the mol ratio of tert.-butyl acetate are 1: (1-5), temperature of reaction is 10-60 ℃.
3. the synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1, it is characterized in that the catalyzer in described step (1) is perchloric acid solution, concentration is 10-50%, and the mol ratio of add-on and described Serine is (0.05-0.5): 1.
4. the synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1; it is characterized in that N-chloracetyl-Serine tert-butyl ester in described step (3) and the mol ratio of sodium ethylate are 1: (1-4); the addition of toluene is every gram of N-chloracetyl-Serine tert-butyl ester of 2-30mL/, and temperature of reaction is 30-110 ℃.
5. the 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 in described step (4) and the mol ratio of sodium borohydride are 1: (0.5-3), the addition of methyl alcohol is every gram of S-5-oxo-morpholinyl carboxylic acid tert-butyl ester of 5-30mL/, and temperature of reaction is 0-40 ℃.
6. the synthetic method of (S)-morpholinyl carboxylic acid as claimed in claim 1, it is characterized in that the hydrogen chloride methanol solution concentration in described step (5) is 30-35%, the addition of hydrogen chloride methanol solution is every gram of 2-20mL/ (S)-morpholinyl carboxylic acid tert-butyl ester, and the addition of methyl alcohol is every gram of 5-30mL/ (S)-morpholinyl carboxylic acid tert-butyl ester.
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| 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 |
| CN103880768B (en) * | 2014-02-26 | 2016-04-13 | 南通大学 | A kind of chemical synthesis process of 3-cyclobutyl morpholine |
| 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 |
Citations (2)
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|---|---|---|---|---|
| US6432947B1 (en) * | 1997-02-19 | 2002-08-13 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as NOS inhibitors |
| CN101305011A (en) * | 2005-09-09 | 2008-11-12 | 史密丝克莱恩比彻姆公司 | Pyridine derivatives and their use in the treatment of psychotic disorders |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6432947B1 (en) * | 1997-02-19 | 2002-08-13 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as NOS inhibitors |
| CN101305011A (en) * | 2005-09-09 | 2008-11-12 | 史密丝克莱恩比彻姆公司 | Pyridine derivatives and their use in the treatment of psychotic disorders |
Non-Patent Citations (4)
| Title |
|---|
| Chiral Synthesis of 3-Substituted Morpholines via Serine Enantiomers and Reductions of 5-Oxomorpholine-3-carboxylates;George R. Brown et al;《J.Chem.Soc.,Perkin Trans.I》;19850101;2577-2580 * |
| Duo Mei et al.Improved Enantioselective Synthesis of Protected (3S,4S)-4-Amino-3,5-dihydroxypentanoic Acid (ADPA).《Synthetic Communications》.2010,第40卷(第8期),1099-1105. |
| GeorgeR.Brownetal.ChiralSynthesisof3-SubstitutedMorpholinesviaSerineEnantiomersandReductionsof5-Oxomorpholine-3-carboxylates.《J.Chem.Soc. Perkin Trans.I》.1985 |
| Improved Enantioselective Synthesis of Protected (3S,4S)-4-Amino-3,5-dihydroxypentanoic Acid (ADPA);Duo Mei et al;《Synthetic Communications》;20100312;第40卷(第8期);1099-1105 * |
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