CN112608359B - Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione - Google Patents

Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione Download PDF

Info

Publication number
CN112608359B
CN112608359B CN202011643946.1A CN202011643946A CN112608359B CN 112608359 B CN112608359 B CN 112608359B CN 202011643946 A CN202011643946 A CN 202011643946A CN 112608359 B CN112608359 B CN 112608359B
Authority
CN
China
Prior art keywords
diene
reaction
hydroxyandrosta
dione
alpha
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.)
Active
Application number
CN202011643946.1A
Other languages
Chinese (zh)
Other versions
CN112608359A (en
Inventor
潘建洪
隋志红
金旦妮
叶有志
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taizhou Xianju Pharmaceutical Co ltd
Original Assignee
Taizhou Xianju Pharmaceutical Co ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Taizhou Xianju Pharmaceutical Co ltd filed Critical Taizhou Xianju Pharmaceutical Co ltd
Priority to CN202011643946.1A priority Critical patent/CN112608359B/en
Publication of CN112608359A publication Critical patent/CN112608359A/en
Application granted granted Critical
Publication of CN112608359B publication Critical patent/CN112608359B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J7/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention discloses a method for preparing 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone, which comprises the following steps: (1) dispersing the ketal protector (I) in an organic solvent, and carrying out a Grignard reaction in a tubular reactor filled with a catalyst; (2) will be describedCarrying out deprotection reaction on the obtained Grignard reaction raw material liquid in a tubular reactor filled with strong acid ion exchange resin to prepare intermediate ketone (II); (3) and (3) carrying out post-treatment on the feed liquid after the deprotection reaction to obtain 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-diketone (III), wherein the reaction formula is as follows:
Figure DDA0002879244940000011
the invention uses the continuous tubular reaction technology to replace the existing interval kettle type reaction to prepare the 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone, is easy to realize the automatic control of the process, is convenient for continuous production and improves the stability of the process.

Description

Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione
Technical Field
The invention relates to a method for preparing 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone.
Background
The 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone is an important intermediate for synthesizing the steroid hormone drug dexamethasone. Clinically, dexamethasone can be used for treating various diseases including severe allergy, asthma, rheumatoid arthritis, laryngitis, cerebral edema and the like, and the latest research shows that dexamethasone is also an effective medicament for treating severe patients with new coronary pneumonia. At present, the production process of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione mainly uses 17 beta-cyano-17 alpha-hydroxyandrosta-4, 9-diene-3-one as a starting material.
Chinese patent CN105440094B discloses a preparation method of 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone, which takes 17 beta-cyano-17 alpha-hydroxyandrostane-4, 9-diene-3-ketone as an initial raw material and obtains a target product through the steps of 3-ketocarbonyl protection, 17-hydroxyl protection, Grignard reaction, deprotection and the like. The method has the advantages of long steps, multi-step protection and deprotection, long production period, high process cost and low total yield. The process route is as follows:
Figure BDA0002879244920000011
in addition to the above-mentioned drawbacks, there are the following problems:
(1) the batch type (kettle type) reaction mode is adopted, the reaction process is difficult to control, the reaction rate is slow, the efficiency is low, and the yield and the quality of the product are unstable.
(2) The reaction activity of the cyano group is poor, a large amount of Grignard reagent is needed to ensure the complete conversion of the raw materials, and the process cost is high.
(3) In the kettle type reactor, the online reaction material amount is large, the material back mixing is serious, and the side reaction is more.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone, which is simple to operate, environment-friendly, low in production cost and suitable for industrialization.
To achieve the above object, the present invention provides a method for preparing 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione, comprising the steps of: (1) dispersing the ketal protector (I) in an organic solvent, and carrying out a Grignard reaction in a tubular reactor filled with a catalyst; (2) carrying out deprotection reaction on the obtained Grignard reaction raw material liquid in a tubular reactor filled with strong acid ion exchange resin to prepare intermediate ketone (II); (3) and (3) carrying out post-treatment on the feed liquid after the deprotection reaction to obtain 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-diketone (III), wherein the reaction formula is as follows:
Figure BDA0002879244920000021
further, the raw material ketal protector (I) is dissolved in an organic solvent and placed in a storage bottle A; placing the Grignard reagent in a storage bottle B; conveying the solutions in the storage bottles A and B into a mixer T through metering pumps P1 and P2 respectively for mixing, continuously feeding the mixed solution into a tubular reactor R1 filled with a Lewis acid catalyst for Grignard reaction, continuously feeding the reacted mixed solution into a tubular reactor R2 filled with strong acid ion exchange resin for deprotection reaction after passing through a connecting valve E, and carrying out post-treatment on the reacted mixed solution to obtain the 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-diketone (III).
Further, the organic solvent is one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, toluene and ethyl acetate.
Further, the Grignard reagent is methyl magnesium chloride or methyl magnesium bromide, and the reaction temperature is 25-110 ℃.
Further, the lewis acid catalyst is one of magnesium chloride, lithium chloride or lithium bromide.
Further, the retention time of the format reaction is 15mins-2 h.
Further, the mass ratio of the ketal protector (I) to the grignard reagent is 1: 2-5.
Further, the retention time of the deprotection reaction is 10mins-2h, and the temperature is 0-80 ℃.
Further, the post-processing step is: adding alkali liquor for neutralization, extracting by using organic solvent, carrying out reduced pressure distillation to recover the organic solvent, and recrystallizing the obtained concentrate by using the organic solvent to obtain white crystals, namely the product 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone is prepared.
Further, the organic solvent for recrystallization is one or a mixed solvent of two or more of methanol, ethanol, water, n-hexane, dichloromethane and ethyl acetate.
Compared with the prior art, the invention has the beneficial effects that:
(1) the continuous tubular reaction technology is used for replacing the existing interval kettle type reaction to prepare the 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone, so that the automatic control of the process is easy to realize, the continuous production is convenient, and the stability of the process is improved. (2) The tubular reaction adopts a plug flow sample injection mode, the material back mixing is less, the mass and heat transfer efficiency is high, the reaction rate is obviously improved, and the side reaction is reduced. (3) The Lewis acid is adopted to catalyze the Grignard reaction of the cyano group, so that the dosage of the Grignard reagent is greatly reduced, the process cost is reduced, and the process safety is improved. (4) The strong acid ion exchange resin is adopted to catalyze the deprotection reaction, so that the reaction efficiency can be obviously improved, and the generation amount of three wastes can be reduced. (5) The tubular reactor R1 filled with Lewis acid catalyst and the tubular reactor R2 filled with strong acid ion exchange resin can be reused, thereby reducing the production cost. Therefore, the method for preparing the 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone by adopting the tubular reactor is essentially different from the traditional interval kettle type reaction, and the continuous flow tubular technology adopted by the invention has better reaction effect.
Drawings
FIG. 1 is a process flow diagram of one embodiment of the present invention.
In the figure: a-reservoir A, B-reservoir B, P1-first metering pump, P2-second metering pump, T-mixer, E-junction valve, R1-tubular reactor 1, R2-tubular reactor R2, C-receiver flask.
Detailed Description
The present invention will now be described in detail with reference to the accompanying drawings.
Example 1
As shown in FIG. 1, ketal protector (I) (10mmol,3.55g) was dissolved in 40mL tetrahydrofuran and placed in reservoir A; methylmagnesium bromide (1mol/L, THF solution) (30mL) was placed in reservoir B. The materials in the storage bottle A and the storage bottle B are respectively conveyed by a metering pump and enter a mixer for mixing, the mixed raw material liquid continuously enters a tubular reactor R1 for Grignard reaction (the inner diameter of the pipeline is 0.31cm, the length of the pipeline is 3m, the pipeline is filled with magnesium chloride, the two ends of the pipeline are sealed by sand, the feeding molar flow ratio of the ketal protective material I and the Grignard reagent is controlled to be 1:3), the temperature of the tubular reactor R1 is kept at 50 ℃, and the retention time is 1 h. The reacted feed liquid passes through a connecting valve E and then enters a tubular reactor R2 to carry out deprotection reaction (the inner diameter of a pipeline is 0.31cm, the length of the pipeline is 2m, strong acid ion exchange resin is filled in the pipeline, two ends of the pipeline are sealed by sand star), the temperature of the tubular reactor R2 is kept at 30 ℃, and the retention time is 30 mins. The reacted feed liquid enters a receiving bottle C, and after the feed liquid in the receiving bottle is completely received, saturated NaHCO is added3The solution was neutralized and extracted with dichloromethane, the organic layer was directly concentrated by distillation, and the remaining oily concentrate was recrystallized from a mixed solvent of n-hexane and ethyl acetate to give 2.95g of yellowish crystals, yield 90%, content 99%.
Example 2
The tubular reactor was recycled 5 times according to the procedure and procedure of example 1, with product yields and purities of each time: (1) the yield is 88 percent, and the content is 99 percent; (2) the yield is 87 percent, and the content is 98 percent; (3) the yield is 90 percent, and the content is 98 percent; (4) the yield is 85 percent, and the content is 99 percent; (5) the yield is 84 percent, and the content is 98 percent;
example 3
Ketal protector (I) (30mmol,10.7g) was dissolved in 100mL of toluene and placed in reservoir A; methylmagnesium bromide (1mol/L, THF solution) (120mL) was placed in reservoir B. The materials of the storage bottle A and the storage bottle B are respectively conveyed by a metering pump and enter a mixer for mixing, the mixed raw material liquid continuously enters a tubular reactor R1 for Grignard reaction (the inner diameter of the pipeline is 0.31cm, the length of the pipeline is 3m, the pipeline is filled with lithium bromide, two ends of the pipeline are sealed by sand, the molar flow ratio of the ketal protective substance to the methyl magnesium chloride is controlled to be 1:4), the temperature of the tubular reactor is kept at 100 ℃, and the retention time of the mixed raw material liquid in the tubular reactor is 30 mins. The reacted feed liquid passes through a connecting valve E and then enters a tubular reactor R2 to carry out deprotection reaction (the inner diameter of a pipeline is 0.31cm, the length of the pipeline is 2m, strong acid ion exchange resin is filled in the pipeline, two ends of the pipeline are sealed by sand star), the temperature of the tubular reactor R2 is kept at 50 ℃, and the retention time is 15 mins. The reacted feed liquid enters a receiving bottle C, and after the feed liquid in the receiving bottle is completely received, saturated NaHCO is added3The solution was neutralized and extracted with dichloromethane, the organic layer was directly concentrated by distillation, and the remaining oily concentrate was recrystallized from a mixed solvent of methanol and water to give 8.37g of yellowish crystals, 85% yield and 99% content.
Example 4
Ketal protector (I) (15mmol,5.3g) was dissolved in 50mL of diethyl ether and placed in reservoir A; methylmagnesium bromide (1mol/L, THF solution) (30mL) was placed in reservoir B. The materials of the storage bottle A and the storage bottle B are respectively conveyed by a metering pump and enter a mixer for mixing, the mixed raw material liquid continuously enters a tubular reactor R1 for Grignard reaction (the inner diameter of the pipeline is 0.31cm, the length of the pipeline is 3m, the pipeline is filled with lithium chloride, two ends of the pipeline are sealed by sand, the molar flow ratio of the ketal protective substance to the methyl magnesium chloride is controlled to be 1:2), the temperature of the tubular reactor is kept at 40 ℃, and the retention time of the mixed raw material liquid in the tubular reactor is 1.5 h. The reacted feed liquid passes through a connecting valve E and then enters a tubular reactor R2 for removalAnd (3) performing protection reaction (the inner diameter of the pipeline is 0.31cm, the length of the pipeline is 2m, the pipeline is filled with strong acid ion exchange resin, two ends of the pipeline are sealed by sand), the temperature of R2 of the tubular reactor is kept at 30 ℃, and the retention time is 15 mins. The reacted feed liquid enters a receiving bottle C, and after the feed liquid in the receiving bottle is completely received, saturated NaHCO is added3The solution was neutralized and extracted with ethyl acetate, the organic layer was directly concentrated by distillation, and the remaining oily concentrate was recrystallized from a mixed solvent of methanol and dichloromethane to give 3.94g of yellowish crystals, 80% yield and 98% content.
Example 5
Following the procedure and procedure of example 1, except using ethyl acetate as the reaction solvent, 2.89g of yellowish crystals were obtained in 88% yield and 98% content.
Example 6
Following the procedure of example 1, except adjusting the Grignard reagent to methyl magnesium chloride, 2.72g of yellowish crystals were obtained in 83% yield with a content of 98%.
Example 7
Following the procedure and procedure of example 1, except that the molar amounts of ketal protector (I) and Grignard reagent were adjusted to 1:5, yellowish crystals were obtained in an amount of 3.05g, yield 93%, content 99%.
Example 8
Following the procedure and procedure of example 1, except that the residence time of the feed solution in tubular reactor R1 was adjusted to 2h and the residence time in tubular reactor R2 was adjusted to 15mins, gave 2.92g of yellowish crystals, 89% yield and 99% content.
Example 9
Following the procedure of example 1 except for adjusting the recrystallization solvent to a mixed solvent of petroleum ether and ethyl acetate, yellowish crystals 2.86g were obtained in a yield of 87% and a content of 99%.
Comparative example
Refer to the preparation method of patent publication CN 105440094B: ketal protector (I) (15mmol,5.3g) was dissolved in 50mL of anhydrous isopropyl ether, N2Under stirring in the atmosphere, 150mL of 2M methyl chloride solution was slowly added dropwiseAfter the dropwise addition of the magnesium, the temperature is gradually increased to reflux, and the reaction is carried out for 20 hours. After the reaction was completed, the material was cooled, and 100mL of saturated ammonium chloride solution was added to quench, and the mixture was allowed to stand for layering, and the aqueous phase was extracted with ethyl acetate (60mL × 3), and then the organic phase was combined, and after the organic phase was concentrated, 50mL of methanol and 4mL of concentrated hydrochloric acid were added, and after stirring under reflux for 15 minutes, 50mL of sodium acetate solution (50%) was added to the organic phase and stirred for 10 minutes. After the organic layer is concentrated until solid is separated out, 50mL of water is added while stirring, the mixture is stirred for 30 minutes, then the filtration is carried out, a filter cake is refluxed and pulped by a mixed solvent of methanol and water (10mL of water and 10mL of methanol), then the cooling suction filtration and the vacuum drying are carried out, and 3.84g of yellowish solid is obtained, the yield is 78%, and the content is 92%. As can be seen from the comparative example, the reaction was carried out in a tank without adding Lewis acid as a catalyst, and the yield and the product purity of the reaction did not reach the level of the present invention, showing that the method of the present invention has great advantages.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims (10)

1. A process for preparing 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione, characterized by the steps of: (1) dispersing the ketal protector (I) in an organic solvent, and carrying out a Grignard reaction in a tubular reactor filled with a catalyst; (2) carrying out deprotection reaction on the obtained Grignard reaction raw material liquid in a tubular reactor filled with strong acid ion exchange resin to prepare intermediate ketone (II); (3) and (3) carrying out post-treatment on the feed liquid after the deprotection reaction to obtain 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-diketone (III), wherein the reaction formula is as follows:
Figure FDA0002879244910000011
2. the process for the preparation of 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione as claimed in claim 1, characterized in that the starting ketal protector (I) is dissolved in an organic solvent and placed in a storage bottle a; placing the Grignard reagent in a storage bottle B; conveying the solutions in the storage bottles A and B into a mixer T through metering pumps P1 and P2 respectively for mixing, continuously feeding the mixed solution into a tubular reactor R1 filled with a Lewis acid catalyst for Grignard reaction, continuously feeding the reacted mixed solution into a tubular reactor R2 filled with strong acid ion exchange resin for deprotection reaction after passing through a connecting valve E, and carrying out post-treatment on the reacted mixed solution to obtain the 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-diketone (III).
3. The method of claim 2, wherein the organic solvent is one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, toluene, and ethyl acetate.
4. The process for the preparation of 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione as claimed in claim 2, wherein the grignard reagent is methyl magnesium chloride or methyl magnesium bromide and the reaction temperature is 25 to 110 ℃.
5. The process for preparing 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione as claimed in claim 2, wherein the lewis acid catalyst is one of magnesium chloride, lithium chloride or lithium bromide.
6. The process for the preparation of 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione as claimed in claim 2, wherein the retention time of the grignard reaction is 15mins-2 h.
7. The method of claim 2, wherein the mass ratio of ketal protector (I) to grignard reagent is 1: 2-5.
8. The process for the preparation of 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione as claimed in claim 2, wherein the deprotection reaction has a retention time of 10mins "2 h and a temperature of 0-80 ℃.
9. The process for the preparation of 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione as claimed in claim 2, characterized in that the post-treatment step is: adding alkali liquor for neutralization, extracting by using organic solvent, carrying out reduced pressure distillation to recover the organic solvent, and recrystallizing the obtained concentrate by using the organic solvent to obtain white crystals, namely the product 17 alpha-hydroxyandrostane-4, 9-diene-3, 20-diketone is prepared.
10. The method for preparing 17 α -hydroxyandrosta-4, 9-diene-3, 20-dione according to claim 9, wherein the organic solvent for recrystallization is one or a mixed solvent of two or more of methanol, ethanol, water, n-hexane, dichloromethane, and ethyl acetate.
CN202011643946.1A 2020-12-31 2020-12-31 Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione Active CN112608359B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011643946.1A CN112608359B (en) 2020-12-31 2020-12-31 Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011643946.1A CN112608359B (en) 2020-12-31 2020-12-31 Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione

Publications (2)

Publication Number Publication Date
CN112608359A CN112608359A (en) 2021-04-06
CN112608359B true CN112608359B (en) 2022-01-28

Family

ID=75253460

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011643946.1A Active CN112608359B (en) 2020-12-31 2020-12-31 Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione

Country Status (1)

Country Link
CN (1) CN112608359B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114437166B (en) * 2022-01-27 2023-11-21 台州仙琚药业有限公司 Synthesis method of 17 beta-cyano-17 alpha-hydroxy-9-dehydroandrostenedione

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2532902C1 (en) * 2013-07-12 2014-11-20 Российская Федерация, от имени которой выступает Министерство промышленности и торговли Российской Федерации (Минпромторг России) Method of obtaining 11beta, 17 alpha, 21-trihydroxy-16alpha-methyl-9alpha-fluoropregna-1,4-diene-3,20-dione (dexamethazone) from phytosterol
CN104774231A (en) * 2014-01-13 2015-07-15 上海医药工业研究院 17alpha-hydroxy-19-norpregn-4,9-diene-3,20-dione preparation process
CN105399791B (en) * 2015-10-27 2017-03-29 江苏远大仙乐药业有限公司 A kind of preparation method of betamethasone intermediate
CN107286216A (en) * 2016-03-31 2017-10-24 天津金耀集团有限公司 Preparation method with multiple alkene steroidal compounds

Also Published As

Publication number Publication date
CN112608359A (en) 2021-04-06

Similar Documents

Publication Publication Date Title
CN103803584B (en) Ammonium bifluoride preparation method
CN101863784A (en) Methods for preparing and extracting betaine and betaine hydrochloride
CN112608359B (en) Process for the preparation of 17 alpha-hydroxyandrosta-4, 9-diene-3, 20-dione
CN101928202B (en) Production method of high-purity 3-chloro-1, 2-propanediol
CN113652171A (en) Method for preparing disproportionated rosin with high dehydroabietic acid content
CN104710402B (en) Dicyclohexyl crown ether synthesis method
CN102794185B (en) Method, catalyst and device for prepareing 1,3-dioxolane
CN111320665A (en) Process for preparing 17 β -cyano-17 α -hydroxy-9-dehydroandrostenedione
CN108947870B (en) Preparation method of bromosartanbiphenyl
EP3896057B1 (en) Method for continuously preparing citalopram diol
CN109438304B (en) Preparation method of 2-chloropropenyl isothiocyanate
CN108047033B (en) Reaction device and method for preparing mandelic acid compound
CN113105517B (en) Synthesis method of androstane-1, 4, 9-triene-3, 17-diketone
CN102060778B (en) Method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester
CN111087319A (en) Method for continuously preparing glycine in alcohol phase
CN102344359B (en) Method for preparing 3-butenoic acid
CN113121532B (en) Preparation method of dye intermediate
CN111393256B (en) Synthetic method of 2,2',3,3',5,5',6,6' -octafluoro-4,4 ' -dibromobiphenyl
CN116947755B (en) Continuous preparation method and device of ethoxyquinoline
CN114031575B (en) Preparation method of ethyl northioxomate
CN111909106B (en) Synthesis method of 4-methyl-5-ethoxy oxazole by continuous saponification and decarboxylation
CN117756632B (en) Purification method for synthesizing methyl acetate by esterification reaction
CN104926856A (en) Falling film continuous preparation method of acyloxysilane
CN109180470B (en) Preparation of 2- (4-bromomethylphenyl) propionic acid by liquid phase circulation method
CN101362772A (en) Method for preparing dibutylmagnesium

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant