CN1986548A - Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane - Google Patents
Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane Download PDFInfo
- Publication number
- CN1986548A CN1986548A CN 200510111853 CN200510111853A CN1986548A CN 1986548 A CN1986548 A CN 1986548A CN 200510111853 CN200510111853 CN 200510111853 CN 200510111853 A CN200510111853 A CN 200510111853A CN 1986548 A CN1986548 A CN 1986548A
- Authority
- CN
- China
- Prior art keywords
- reaction
- tertbutyloxycarbonyl
- dicyclo
- oxa
- heptane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pyrrole Compounds (AREA)
Abstract
The present invention relates to continuous industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane. 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] the continuous synthetic industrialized process for preparing of heptane.
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: 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; The N-tertbutyloxycarbonyl that a kind of whole yield is higher, preparation cost is lower-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is provided.
Technical scheme of the present invention:
The present invention is a raw material with L-oxyproline conventional, that be easy to get, obtains N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane by esterification, tertbutyloxycarbonyl protection, tosic acid esterification, hydrolysis with after lactonizing.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we at first adopt continuous synthetic method that the L-oxyproline is carried out esterification, tertbutyloxycarbonyl protection and tosic acid esterification.
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 preferred initial reaction temperature is room temperature (20 ℃-25 ℃); Reacted crude product is directly gone up protection, blocking group reagent BOC acid anhydrides, and auxiliary addition agent is selected triethylamine for use, reaction solvent can be used methyl alcohol, 1, a kind of in 4-dioxane and the methylene dichloride, temperature of reaction is 0 ℃-70 ℃, preferred initial reaction temperature is room temperature (20 ℃-25 ℃); Last directly tosic acid esterification, adopt Tosyl chloride, auxiliary addition agent is selected pyridine or triethylamine for use, and reaction solvent is selected a kind of in tetrahydrofuran (THF), toluene and the methylene dichloride for use, temperature of reaction is 0 ℃-100 ℃, and preferred initial reaction temperature is room temperature (20 ℃-25 ℃).Three step yields are 81～89%.
Then, we are hydrolyzed continuously and react and lactonization reaction, in hydrolysis reaction, we select alkali commonly used and that be easy to get for use, and as sodium hydroxide, potassium hydroxide and lithium hydroxide etc., reaction solvent is selected from water, methyl alcohol, ethanol, a kind of in acetone and the tetrahydrofuran (THF), temperature is a room temperature to 78 ℃.Directly carry out lactonization reaction then, reaction reagent can be selected a kind of in yellow soda ash, salt of wormwood, sodium hydroxide and the potassium hydroxide for use, it is room temperature to 110 ℃ that reaction solvent can be used a kind of in acetone, methylethylketone, methyl isopropyl Ketone and the methyl iso-butyl ketone (MIBK), temperature of reaction.The two-step reaction yield is 82～87%.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally; it has adopted, and economy is easy to get, the raw material L-oxyproline of energy large-scale production obtains N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2 through esterification, tertbutyloxycarbonyl protection, tosic acid esterification, hydrolysis with after lactonizing; 2; 1] heptane; its overall yield reaches 66～77%, and the present invention reacts easy control, and preparation cost is lower; 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, was concentrated into dried thick product L-L-Hydroxyproline methyl ester hydrochloride, directly it was dissolved in methyl alcohol (6.0L), add triethylamine (680g under the room temperature, 6.3mol) and the BOC acid anhydrides (520g 2.4mol), reacts after 1 hour, concentrate and do, obtain thick product N-tertbutyloxycarbonyl-L-L-Hydroxyproline methyl ester, it is dissolved in methylene dichloride (3L), add anhydrous pyridine (237g under the room temperature, 3.0mol) and Tosyl chloride (437g, 2.3mol), reacted 2 hours, add saturated sodium bicarbonate aqueous solution (3L), layering, organic phase water (3L) washing again is 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
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (710g, 1.78mol) be dissolved in methyl alcohol (3.5L), (5N 0.4L), stirs after 3 hours to add potassium hydroxide aqueous solution under the room temperature, it is 4～5 that 1N hydrochloric acid is regulated pH, separate out solid, filter, the thick product that obtains is dissolved in acetone (5L), add yellow soda ash (212g, 2.0mol), refluxed cool to room temperature 6 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 (330g, 1.55mol). productive rate: 87%.
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 (72g, 0.55mol) be dissolved in anhydrous methanol (0.48L), drip the vitriol oil (60g under the room temperature, 0.6mol), reaction solution stirring at room 5 hours concentrates as for getting thick product L-L-Hydroxyproline methyl ester hydrochloride, directly it is dissolved in methyl alcohol (1.44L), add triethylamine (163g under the room temperature, 1.5mol) and the BOC acid anhydrides (1245g 0.58mol), reacts after 1 hour, concentrate and do, obtain thick product N-tertbutyloxycarbonyl-L-L-Hydroxyproline methyl ester, it is dissolved in toluene (0.72L), add anhydrous pyridine (56.9g under the room temperature, 0.72mol) and Tosyl chloride (104g, 0.55mol), reacted 2 hours, add saturated sodium bicarbonate aqueous solution (0.72L), layering, organic phase water (0.72L) washing again is concentrated into dried crude product, behind methyl tertiary butyl ether (0.6L) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (193g, 0.48mol), productive rate: 88%.Its test data is shown in above-mentioned embodiment 1 the first step.
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (852g, 2.14mol) be dissolved in tetrahydrofuran (THF) (6.0L), (1N 3L), stirs after 3 hours to add lithium hydroxide aqueous solution under the room temperature, it is 4～5 that 1N hydrochloric acid is regulated pH, separate out solid, filter, the thick product that obtains is dissolved in methylethylketone (6L), add potassium hydroxide (345g, 2.5mol), refluxed cool to room temperature 6 hours, add water (6L) and ethyl acetate (3L) layering, organic phase is concentrated into dried thick product, and 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%.Its test data is shown in above-mentioned embodiment 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 dried thick product L-L-Hydroxyproline methyl ester hydrochloride, directly it is dissolved in 1,4-dioxane (60mL), (6.8g is 63mmol) with BOC acid anhydrides (5.2g to add triethylamine under the room temperature, 24mmol), react after 1 hour, concentrate and do, obtain thick product N-tertbutyloxycarbonyl-L-L-Hydroxyproline methyl ester, it is dissolved in tetrahydrofuran (THF) (30mL), add under the room temperature anhydrous triethylamine (3.0g, 30mol) and Tosyl chloride (4.4g, 23mmol), reacted 2 hours, add saturated sodium bicarbonate aqueous solution (30mL), layering, organic phase water (30mL) washing again, be concentrated into dried crude product, behind methyl tertiary butyl ether (25mL) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (7.6g, 19.0mmol), productive rate: 83%.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
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (64g, 0.16mol) add aqueous sodium hydroxide solution (5N under the room temperature, 0.04L), stir after 3 hours, it is 4～5 that 1N hydrochloric acid is regulated pH, separates out solid, filter, the thick product that obtains is dissolved in methyl iso-butyl ketone (MIBK) (0.5L), and adding salt of wormwood (25g, 0.18mol), refluxed 6 hours, cool to room temperature adds water (300mL) layering, and organic phase is concentrated into dried thick product, the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (28g, 0.13mol). productive rate: 82%.Its test data is shown in above-mentioned embodiment 1.
Embodiment 4
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
Prepare corresponding product according to the described continuous esterification of the first step in the foregoing description 1, tertbutyloxycarbonyl protection and tosic acid esterification technique condition and operation steps, 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
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (42.6g, 0.11mol) be dissolved in ethanol (0.2L), (5N 0.3L), stirs after 3 hours to add aqueous sodium hydroxide solution under the room temperature, it is 4～5 that 1N hydrochloric acid is regulated pH, separate out solid, filter, the thick product that obtains is dissolved in methyl isopropyl Ketone (0.3L), add sodium hydroxide (4.8g, 0.12mol), refluxed cool to room temperature 6 hours, add water (3L) layering, organic phase concentrates as for getting thick product, and the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (19g, 0.09mol). productive rate: 84%.Its test data is shown in above-mentioned embodiment 1.
Claims (10)
1, N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] the continuous synthetic industrialized process for preparing of heptane; with L-oxyproline conventional, that be easy to get is raw material; it is characterized in that; the L-oxyproline obtains N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane by esterification, tertbutyloxycarbonyl protection, tosic acid esterification, hydrolysis with after lactonizing.
2, N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane 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] the continuous synthetic industrialized process for preparing of heptane; it is characterized in that, the L-oxyproline is carried out esterification, tertbutyloxycarbonyl protection and tosic acid esterification with continuous synthetic method.
4, N-tertbutyloxycarbonyl according to claim 1 and 2-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] the continuous synthetic industrialized process for preparing of heptane, it is characterized in that, in described esterification reaction of organic acid, reaction solvent is a methyl alcohol, 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 ℃.
5, N-tertbutyloxycarbonyl according to claim 4-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that initial reaction temperature is a room temperature.
6, N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] the continuous synthetic industrialized process for preparing of heptane; it is characterized in that, in the tertbutyloxycarbonyl protective reaction, blocking group reagent BOC acid anhydrides; auxiliary addition agent is selected triethylamine for use; reaction solvent is selected from methyl alcohol, 1, a kind of in 4-dioxane and the methylene dichloride, and temperature of reaction is 0 ℃-70 ℃.
7, N-tertbutyloxycarbonyl according to claim 6-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that initial reaction temperature is a room temperature.
8, N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] the continuous synthetic industrialized process for preparing of heptane, it is characterized in that, in the tosic acid esterification reaction, adopt Tosyl chloride, auxiliary addition agent is selected pyridine or triethylamine for use, reaction solvent is selected a kind of in tetrahydrofuran (THF), toluene and the methylene dichloride for use, and temperature of reaction is 0 ℃-100 ℃.
9, N-tertbutyloxycarbonyl according to claim 8-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that initial reaction temperature is a room temperature.
10, N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] the continuous synthetic industrialized process for preparing of heptane, it is characterized in that, described hydrolysis reaction and lactonization reaction carry out continuously, in hydrolysis reaction, used alkali is selected from sodium hydroxide, a kind of in potassium hydroxide and the lithium hydroxide, reaction solvent is selected from water, methyl alcohol, ethanol, a kind of in acetone and the tetrahydrofuran (THF), temperature of reaction is a room temperature to 78 ℃, directly carries out lactonization reaction then, and reaction reagent is selected from yellow soda ash, salt of wormwood, a kind of in sodium hydroxide and the potassium hydroxide, reaction solvent is selected from acetone, methylethylketone, a kind of in methyl isopropyl Ketone and the methyl iso-butyl ketone (MIBK), temperature of reaction is a room temperature to 110 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510111853A CN1986548B (en) | 2005-12-22 | 2005-12-22 | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510111853A CN1986548B (en) | 2005-12-22 | 2005-12-22 | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1986548A true CN1986548A (en) | 2007-06-27 |
| CN1986548B CN1986548B (en) | 2010-05-26 |
Family
ID=38183504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200510111853A Expired - Fee Related CN1986548B (en) | 2005-12-22 | 2005-12-22 | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1986548B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503891A (en) * | 2014-09-23 | 2016-04-20 | 常州合全药业有限公司 | 5-tert-butyloxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid synthesis method |
| CN113501946A (en) * | 2021-08-04 | 2021-10-15 | 南京先进生物材料与过程装备研究院有限公司 | Method for synthesizing proline-based polymer |
| CN115572251A (en) * | 2022-10-18 | 2023-01-06 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethyloxycarbonyl-4-tert-butyloxycarbonyl-D-proline |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| JP2005220079A (en) * | 2004-02-05 | 2005-08-18 | Shionogi & Co Ltd | Synthesis of pyrrolidine compound and crystal therefor |
-
2005
- 2005-12-22 CN CN200510111853A patent/CN1986548B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503891A (en) * | 2014-09-23 | 2016-04-20 | 常州合全药业有限公司 | 5-tert-butyloxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid synthesis method |
| CN105503891B (en) * | 2014-09-23 | 2018-03-27 | 常州合全药业有限公司 | A kind of synthetic method of the carboxylic acid of 5 tertbutyloxycarbonyl, 2 oxa-, 5 azabicyclic [2.2.1] heptane 1 |
| CN113501946A (en) * | 2021-08-04 | 2021-10-15 | 南京先进生物材料与过程装备研究院有限公司 | Method for synthesizing proline-based polymer |
| CN115572251A (en) * | 2022-10-18 | 2023-01-06 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethyloxycarbonyl-4-tert-butyloxycarbonyl-D-proline |
| CN115572251B (en) * | 2022-10-18 | 2024-03-22 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethoxycarbonyl-4-tert-butoxycarbonylamino-D-proline |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1986548B (en) | 2010-05-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101759631A (en) | Method for preparing butyrate clevidipine | |
| CN108610324B (en) | Preparation method of vinyl sulfate | |
| CN1268611C (en) | Method of preparing 4-hydroxy pyrrolidone-2-acetamine | |
| CN1986548B (en) | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane | |
| CN102757379B (en) | Preparation method of alvimopan | |
| CN106749335B (en) | A kind of preparation method and application of halogenated oxygen cephalo-type intermediate | |
| CN104744390A (en) | Preparation method of ezetimibe internmediate ketone | |
| CN108530402B (en) | Preparation method of (R) -3-propyl-gamma-butyrolactone | |
| CN114736151B (en) | Preparation method of Pa Luo Weide key intermediate and structural formula of compound | |
| EP4130020A1 (en) | Novel method for preparing inotodiol | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN1986547B (en) | Industrial preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptance in one cauldron | |
| CN114717280A (en) | Synthesis method of monopilavir | |
| CN114057767A (en) | Preparation method of temsirolimus | |
| CN113372375A (en) | Preparation method of temsirolimus intermediate | |
| CN101805380B (en) | Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate | |
| CN106554301A (en) | A kind of preparation method of BMS-477118 key intermediate | |
| US6313321B1 (en) | Process for preparing β-hydroxy-γ-butyrolactones and β-(meth)acryloyloxy-γ-butrolactones | |
| CN100537584C (en) | Branched polyhydroxy pyrrole derivatives and preparation method and application | |
| CN106496220B (en) | A kind of preparation method of lysergol | |
| CN1470506A (en) | Method for synthesizing polycarbo amide | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| EP1053244A1 (en) | Glycosidation of 4,5-epoxymorphinan-6-ols | |
| CN111777554A (en) | Method for synthesizing cisatracurium besilate | |
| JPH1121267A (en) | Production of (-)-shikimic acid or precursor of the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100526 Termination date: 20141222 |
|
| EXPY | Termination of patent right or utility model |