CN114349631A - Preparation method and application of 4-methoxy crotonic acid - Google Patents
Preparation method and application of 4-methoxy crotonic acid Download PDFInfo
- Publication number
- CN114349631A CN114349631A CN202210043110.0A CN202210043110A CN114349631A CN 114349631 A CN114349631 A CN 114349631A CN 202210043110 A CN202210043110 A CN 202210043110A CN 114349631 A CN114349631 A CN 114349631A
- Authority
- CN
- China
- Prior art keywords
- glyoxylic acid
- acid
- methoxy
- methyl
- crotonic acid
- 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.)
- Pending
Links
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 29
- 239000000047 product Substances 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000011574 phosphorus Substances 0.000 claims abstract description 24
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 24
- 239000013067 intermediate product Substances 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 13
- 230000011987 methylation Effects 0.000 claims abstract description 8
- 238000007069 methylation reaction Methods 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 230000001603 reducing effect Effects 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 claims description 15
- JMXSTMJTPSFRNI-ONEGZZNKSA-N methyl (e)-4-methoxybut-2-enoate Chemical compound COC\C=C\C(=O)OC JMXSTMJTPSFRNI-ONEGZZNKSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 239000012022 methylating agents Substances 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 159000000011 group IA salts Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000007031 hydroxymethylation reaction Methods 0.000 description 2
- MCVVUJPXSBQTRZ-ONEGZZNKSA-N methyl (e)-but-2-enoate Chemical compound COC(=O)\C=C\C MCVVUJPXSBQTRZ-ONEGZZNKSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- ZOWMFFSGFIGXPJ-UHFFFAOYSA-N C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C(C)=O Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C(C)=O ZOWMFFSGFIGXPJ-UHFFFAOYSA-N 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- RWIKCBHOVNDESJ-NSCUHMNNSA-N methyl (e)-4-bromobut-2-enoate Chemical compound COC(=O)\C=C\CBr RWIKCBHOVNDESJ-NSCUHMNNSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method and application of 4-methoxy crotonic acid, relating to the technical field of organic synthesis and comprising the following steps: after the reaction of glyoxylic acid and a phosphorus reagent, aldehyde group reduction, hydroxyl methylation and hydrolysis are carried out to obtain the 4-methoxy crotonic acid. The invention solves the technical problems of high cost and complex process of synthesizing 4-methoxy crotonic acid and harmfulness of intermediate products in the prior art, and achieves the technical effects of low cost, simple process operation and high purity of obtained products of synthesizing 4-methoxy crotonic acid.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method and application of 4-methoxy crotonic acid.
Background
4-methoxy crotonic acid, with the chemical formula 4-methoxy-2-alkene butyric acid, is a very common chemical intermediate. PFIZER company (WO2009/007814A1) invented a new intraocular pressure controlling drug NO-CAIs, and methyl 4-methoxycrotonate is one of the main raw materials for synthesizing NO-CAIs. The structure of 4-methoxycrotonic acid is as follows:
the prior art reports a synthesis scheme of methyl 4-methoxycrotonate:
the scheme takes methyl crotonate as an initial raw material, and obtains 4-methyl bromocrotonate by reacting with N-bromosuccinimide (NBS), and then reacting with methanol and calcium carbonate to obtain the 4-methyl methoxycrotonate. However, the intermediate product 4-methyl bromocrotonate generated in the above way has strong irritation and sensitization to skin, and has great harm to factory production workers; in addition, N-bromosuccinimide (NBS) is expensive and not suitable for large-scale industrial production.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
An object of the present invention is to provide a process for producing 4-methoxycrotonic acid, which can produce a target product relatively easily at low cost and can produce a product having high purity and small single impurity.
The second purpose of the invention is to provide the application of the preparation method of the 4-methoxy crotonic acid in the synthesis of the medicine.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
in a first aspect, the present invention provides a method for preparing 4-methoxycrotonic acid, comprising the steps of:
after the reaction of glyoxylic acid and a phosphorus reagent, reducing aldehyde group, carrying out hydroxyl methylation and hydrolyzing to obtain 4-methoxy crotonic acid;
the phosphorus reagent includes a compound represented by the following general formula (1):
wherein R is1、R2、R3Independently are alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl.
Further, the preparation method comprises the following steps:
A. reacting glyoxylic acid with a phosphorus reagent under an alkaline condition to obtain an intermediate product;
B. reducing aldehyde groups of the intermediate product obtained in the step A into hydroxyl groups by using a reducing reagent to obtain a reducing product;
C. carrying out hydroxyl methylation on the reduction product obtained in the step B by using a methylating agent to obtain 4-methoxy methyl crotonate;
D. and D, carrying out alkaline hydrolysis on the methyl 4-methoxycrotonate obtained in the step C to obtain 4-methoxycrotonic acid.
Further, the glyoxylic acid comprises glyoxylic acid monohydrate.
Further, the molar ratio of the glyoxylic acid monohydrate to the phosphorus reagent is 1: 1-2;
further preferably, the molar ratio of the glyoxylic acid monohydrate to the phosphorus reagent is 1: 1.2 to 1.5.
Further, the alkali under the alkaline condition in the step a includes at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and is preferably sodium hydroxide.
Further, the molar ratio of the intermediate product to the reducing agent in the step B is 1: 0.5-2, preferably 1: 1 to 1.5, and more preferably 1: 1.3.
further, the reducing agent comprises at least one of sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, zinc powder, palladium carbon and platinum, and preferably zinc powder.
Further, the methylating agent in step C comprises at least one of methanol, methyl iodide, dimethyl sulfate and methyl trifluoromethanesulfonate.
Further, the alkali for alkali hydrolysis in step D comprises at least one of lithium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
In a second aspect, the present invention provides the use of a process for the preparation of 4-methoxycrotonic acid as described in any one of the preceding aspects in the synthesis of a medicament.
Compared with the prior art, the invention has at least the following beneficial effects:
the preparation method of 4-methoxy crotonic acid provided by the invention comprises the steps of reacting low-cost glyoxylic acid with a phosphorus reagent to obtain an intermediate product, and then reducing aldehyde groups, carrying out hydroxy methylation and hydrolyzing to obtain 4-methoxy crotonic acid; the raw material glyoxylic acid is cheap and easy to obtain, the reaction steps are short, and the operation is simple, so the production cost is reduced; the preparation method is more beneficial to industrial production, the quality of reaction products in each step is controllable, and the products have high purity and small single impurity.
The application of the preparation method of 4-methoxy crotonic acid in drug synthesis provided by the invention has the same advantages as the preparation method, and is not repeated herein.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a reaction scheme for synthesizing 4-methoxycrotonic acid according to an embodiment of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
According to a first aspect of the present invention, there is provided a method for producing 4-methoxycrotonic acid, comprising the steps of:
after the reaction of glyoxylic acid and a phosphorus reagent, reducing aldehyde group, carrying out hydroxyl methylation and hydrolyzing to obtain 4-methoxy crotonic acid;
in the present invention, the phosphorus reagent includes a compound represented by the following general formula (1):
wherein R is1、R2、R3Independently are alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl.
The raw material glyoxylic acid is cheap and easy to obtain, the reaction steps are short, and the operation is simple, so the production cost is reduced; the preparation method is more beneficial to industrial production, the quality of reaction products in each step is controllable, and the products have high purity and small single impurity; the inventor discovers through screening of a large number of synthetic routes and conditions that compared with a halogenated product obtained by substituting N-bromosuccinimide (NBS) or other halogenated reagents in the traditional synthetic route, the aldehyde compound obtained by the reaction of glyoxylic acid and a phosphorus reagent is easier to purify and is more beneficial to improving the quality of the product.
In a preferred embodiment, the preparation method of the present invention comprises the steps of:
A. reacting glyoxylic acid with a phosphorus reagent under an alkaline condition to obtain an intermediate product;
B. reducing aldehyde groups of the intermediate product obtained in the step A into hydroxyl groups by using a reducing reagent to obtain a reducing product;
C. carrying out hydroxyl methylation on the reduction product obtained in the step B by using a methylating agent to obtain 4-methoxy methyl crotonate;
D. and D, carrying out alkaline hydrolysis on the methyl 4-methoxycrotonate obtained in the step C to obtain 4-methoxycrotonic acid.
In the step A, glyoxylic acid and a phosphorus reagent react under an alkaline condition to generate an intermediate aldehyde compound; under the alkaline condition, glyoxylic acid generates salt, thereby protecting the carboxyl functional group of the glyoxylic acid; meanwhile, the alkaline environment for the reaction of the phosphorus reagent and the aldehyde group is ensured, and the purification treatment of the post-treatment is also facilitated; the alkaline substance used for creating alkaline conditions in the present invention includes, but is not limited to, at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide.
In a preferred embodiment, the glyoxylic acid in step a of the present invention includes, but is not limited to, glyoxylic acid monohydrate; since glyoxylic acid is conventionally in the form of glyoxylic acid monohydrate or an aqueous solution of glyoxylic acid, the water content of glyoxylic acid monohydrate consumes a part of the phosphorus reagent, the molar ratio of glyoxylic acid monohydrate to the phosphorus reagent in the present invention is 1: 1-2, typically but not limited to, in a molar ratio of, for example, 1: 1. 1: 1.2, 1: 1.4, 1: 1.6, 1: 1.8, 1: 2, preferably 1: 1.2 to 1.5.
In step B of the present invention, the molar ratio of the intermediate product to the reducing agent is 1: 0.5 to 2, typically but not limited to, in a molar ratio of, for example, 1: 0.5, 1: 0.8, 1: 1. 1: 1.2, 1: 1.4, 1: 1.6, 1: 1.8, 1: 2, preferably 1: 1 to 1.5, and more preferably 1: 1.3; the reducing agent in step B of the present invention includes, but is not limited to, at least one of sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, zinc powder, palladium carbon, and platinum, preferably zinc powder; the invention can also realize hydrogenation reduction of aldehyde group by using palladium carbon or platinum under the condition of hydrogen. The reducing reagent selected by the invention can better realize the reducing effect of the aldehyde compound and obtain a reducing product reduced into hydroxyl.
In step C of the present invention, the methylating agent includes but is not limited to at least one of methanol, methyl iodide, dimethyl sulfate and methyl trifluoromethanesulfonate, and the methylating agent selected in the present invention can preferably implement the hydroxymethylation reaction to obtain methyl 4-methoxycrotonate.
In step D of the present invention, the methyl 4-methoxycrotonate is preferably subjected to alkaline hydrolysis in a system of alcohol, water and an alkali or an alkaline salt to obtain 4-methoxycrotonate; wherein, the alcohol includes but is not limited to at least one of methanol, ethanol and isopropanol; the base includes, but is not limited to, at least one of lithium hydroxide, calcium hydroxide, potassium hydroxide, and sodium hydroxide; the basic salt includes, but is not limited to, at least one of sodium carbonate, potassium carbonate, and cesium carbonate. The alkali or alkaline salt selected by the invention can better hydrolyze the 4-methoxy crotonic acid methyl ester to obtain the 4-methoxy crotonic acid.
In conclusion, the invention uses cheap glyoxylic acid and phosphorus reagent to react to obtain an intermediate aldehyde compound, and the aldehyde compound is subjected to aldehyde group reduction, hydroxyl methylation and hydrolysis to obtain the 4-methoxy crotonic acid.
A typical preparation method of 4-methoxy crotonic acid, as shown in figure 1, comprises the following steps:
s1: under the protection of argon, adding glyoxylic acid into a reactor, adding acetonitrile serving as a solvent, cooling to below 10 ℃, adding sodium hydroxide into the system after the temperature is stable, adding triphenylphosphine acetaldehyde into the system after the system is clear, reacting for 6-8 hours, adding water into the system, separating the solution, extracting the organic phase twice with water, combining the aqueous phase, adjusting the pH value of the aqueous phase to 3-4 with dilute hydrochloric acid, extracting the aqueous phase for a plurality of times with methyl tert-butyl ether, separating the solution, washing the organic phase for a plurality of times with a 10% sodium sulfate solution, drying and desolventizing to obtain an intermediate aldehyde compound;
s2: under the protection of argon, adding water and glacial acetic acid into a reactor to prepare a glacial acetic acid aqueous solution, and then mixing the aldehyde compound of the intermediate product obtained in the step S1 and zinc powder according to the molar ratio of 1: 1.2 adding the mixture into the glacial acetic acid aqueous solution, heating for reaction, cooling after the reaction is finished, adding sodium bicarbonate to adjust the pH to 7-8, adding ethyl acetate into the system to extract a water phase, and combining organic phases to obtain a reduction product after aldehyde groups are reduced into hydroxyl groups;
s3: under the protection of argon, the reduction product obtained in the step S2 and sodium hydroxide are mixed according to the molar ratio of 1: 3, adding the mixture into a reactor, adding acetone serving as a solvent for dissolving, cooling to 0-5 ℃, dropwise adding dimethyl sulfate into the system, controlling the temperature to be not more than 10 ℃, heating to reflux after dropwise adding, stirring for reacting until the solution is clear, quenching the reaction with saturated saline solution after the reaction is finished, demixing, desolventizing and concentrating an organic phase to obtain 4-methoxy methyl crotonate, and separating a crude product by using a silica gel column (silica gel, leacheate is n-heptane and ethyl acetate, and the proportion is 100: 5);
s4: dissolving the methyl 4-methoxycrotonate obtained in the step S3 in dichloromethane, adding sodium hydroxide, adding water, stirring for reaction, separating liquid after the reaction is finished, collecting a water phase, adjusting the pH to 2-3 with hydrochloric acid, extracting the water phase with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and desolventizing to obtain the 4-methoxycrotonate.
According to the second aspect of the invention, the application of the preparation method of 4-methoxy crotonic acid in drug synthesis is provided, and the preparation method has the characteristics of low cost, short reaction steps, simple process operation and high product quality.
The invention is further illustrated by the following examples. The materials in the examples are prepared according to known methods or are directly commercially available, unless otherwise specified.
Example 1
S1: under the protection of argon, adding 10g of glyoxylic acid monohydrate into a reactor, adding 100mL of acetonitrile for dissolving, cooling to below 10 ℃, adding 4.35g of sodium hydroxide into the system after the temperature is stable, adding 43g of triphenylphosphinyl acetaldehyde into the system after the system is clear, reacting for 6-8 hours, adding 100mL of water into the system, separating, extracting an organic phase twice by using 40mL of a water phase, combining the water phases, adjusting the pH value of the water phase to 3-4 by using dilute hydrochloric acid, extracting the water phase three times by using 40mL of methyl tert-butyl ether, separating, washing the organic phase twice by using 10% sodium sulfate solution 50mL each time, drying and desolventizing to obtain 9.6g of an intermediate aldehyde compound, wherein the yield is 88.32%;
s2: under the protection of argon, adding 120mL of purified water and 20mL of glacial acetic acid into a reactor to prepare a glacial acetic acid aqueous solution, then adding an aldehyde compound (20g, 0.2mol, 1eq.) as an intermediate product obtained in the step S1 and zinc powder (15.6g, 0.24mol, 1.2eq.) into the glacial acetic acid aqueous solution, heating to 60 ℃ for reaction, cooling after the reaction is finished, adding sodium bicarbonate to adjust the pH to be 7-8, adding ethyl acetate into the system for three times with each 40mL of an extraction aqueous phase, and combining organic phases to obtain 17.8g of a reduction product with the aldehyde group reduced to hydroxyl, wherein the yield is 89%;
s3: under the protection of argon, adding the reduction product (10g, 0.1mol, 1eq.) obtained in the step S2 and sodium hydroxide (12g, 0.3mol, 3eq) into a reactor, adding 100mL of acetone, cooling to 0-5 ℃, dropwise adding dimethyl sulfate (56.7g, 0.45mol, 4.5eq) into the system, controlling the temperature to be not more than 10 ℃, heating to reflux after dropwise adding is finished, reacting under stirring until the raw materials disappear, quenching the system by using 100mL of saturated saline solution after the reaction is finished, demixing, desolventizing and concentrating the organic phase to obtain 4-methoxy methyl crotonate, and purifying the crude product by using a silica gel column (the eluent is n-heptane and ethyl acetate, the ratio is 100: 5) to obtain 11.8g of a colorless oily product, wherein the yield is 90.6%;
s4: adding 130g of 4-methoxy crotonic acid methyl ester into 2000mL of dichloromethane, stirring for dissolving, adding sodium hydroxide (120g, 3.0eq) into the system, adding 800mL of purified water, stirring for reacting for 4 hours, separating liquid after the reaction is finished, collecting an aqueous solution after layering, adjusting the pH of the obtained aqueous solution to 2-3 by hydrochloric acid, extracting the aqueous phase three times by 300mL of ethyl acetate each time, combining organic phases, drying by using anhydrous sodium sulfate, and then desolventizing to obtain 120.5g of 4-methoxy crotonic acid, wherein the yield is 83.4%.
Example 2
S1: under the protection of argon, adding 100g of glyoxylic acid monohydrate into a reactor, adding 1000mL of acetonitrile for dissolving, cooling to below 10 ℃, adding 44.61g of sodium hydroxide into the system after the temperature is stable, adding 450g of triphenylphosphinyl acetaldehyde into the system after the system is clear, reacting for 6-8 hours, adding 1500mL of water into the system, separating, extracting an organic phase twice by using 400mL of water, combining aqueous phases, adjusting the pH value of the aqueous phase system to 3-4 by using dilute hydrochloric acid, extracting the aqueous phase three times by using 500mL of methyl tert-butyl ether, separating, washing the organic phase twice by using 10% sodium sulfate solution every 500mL, drying and desolventizing to obtain 95.2g of an intermediate aldehyde compound with the yield of 87.58%;
s2: under the protection of argon, adding 200mL of purified water and 40mL of glacial acetic acid into a reactor to prepare a glacial acetic acid aqueous solution, then adding an aldehyde compound (30.0g, 0.3mol and 1eq) of the intermediate product obtained in the step S1 into the glacial acetic acid aqueous solution, adding 23.4g (0.36mol and 1.2eq) of zinc powder into the system in batches at room temperature, heating to 60 ℃ for reaction, cooling after the reaction is finished, adding sodium bicarbonate to adjust the pH to be 7-8, adding ethyl acetate into the system for three times for 60mL of extraction aqueous phase each time, and combining organic phases to obtain 27.1g of a reduction product obtained after aldehyde is reduced into hydroxyl, wherein the yield is 91%;
s3: under the protection of argon, adding the reduction product (120g, 1.2mol, 1.2eq.) obtained in the step S2 and potassium carbonate (393g, 3.6mol, 3eq) into a reactor, adding 1500mL of acetone for dissolving, cooling to 0-5 ℃, dropwise adding dimethyl sulfate (680.4g, 5.4mol, 4.5eq) into the system, controlling the temperature to be not more than 10 ℃, heating to reflux after dropwise adding is finished, reacting under stirring until the raw materials disappear, quenching the system by 1000mL of saturated saline solution after the reaction is finished, demixing, desolventizing and concentrating the organic phase to obtain methyl 4-methoxycrotonate, separating the crude product by using a silica gel column (the eluent is n-heptane and ethyl acetate, the ratio is 100: 5) to obtain 113.6g of a colorless oily product, detecting the purity of the product by HPCL to be more than 99.5%, the single impurity to be less than 0.1%, and the yield to be 87.4%;
s4: adding 200g of methyl 4-methoxycrotonate into 3500mL of dichloromethane, stirring for dissolving, adding sodium hydroxide (175g and 3.0eq) into the system, adding 1600mL of purified water, stirring for reacting for 4 hours, separating liquid after reaction, collecting aqueous solution after layering, adjusting the pH of the obtained aqueous solution to 2-3 by using hydrochloric acid, extracting the aqueous phase by using ethyl acetate for 500mL for three times, combining organic phases, drying by using anhydrous sodium sulfate, and desolventizing to obtain 194.7g of 4-methoxycrotonate, wherein the yield is 87.6%.
Example 3
This example is different from example 1 in that the phosphorus reagent used in step S1 of this example is trimethylphosphine acetaldehyde, and the molar ratio of glyoxylic acid monohydrate to trimethylphosphine acetaldehyde is 1: 1.4, obtaining an intermediate aldehyde compound with the yield of 82.2 percent, and obtaining 4-methoxy crotonic acid by referring to example 1 in other subsequent steps.
Example 4
This example differs from example 1 in that the phosphorus reagent used in step S1 of this example is tributylphosphinyl acetaldehyde, and the molar ratio of glyoxylic acid monohydrate to tributylphosphinyl acetaldehyde is 1: 1.3, obtaining an intermediate aldehyde compound with the yield of 83.6 percent, and obtaining 4-methoxy crotonic acid by referring to example 1 in other subsequent steps.
Example 5
This example differs from example 1 in that the phosphorus reagent used in step S1 of this example is tricyclohexylphosphinoacetaldehyde, and the molar ratio of glyoxylic acid monohydrate to tricyclohexylphosphinoacetaldehyde is 1: 1.3, obtaining an intermediate aldehyde compound with the yield of 83.5 percent, and obtaining 4-methoxy crotonic acid by referring to example 1 in other subsequent steps.
Example 6
The difference between this example and example 1 is that the reducing agent used in step S2 in this example is sodium borohydride, and the molar ratio of the intermediate aldehyde compound to sodium borohydride is 1: 0.6, to obtain a reduction product with a yield of 89.4%, followed by other steps with reference to example 1, to obtain 4-methoxycrotonic acid.
Example 7
The difference between this example and example 1 is that the reducing agent used in step S2 in this example is palladium carbon/hydrogen, and the molar ratio of the aldehyde-based compound as the intermediate product to palladium carbon is 1: 0.05, to obtain a reduction product with a yield of 89.3%, followed by other steps with reference to example 1, to obtain 4-methoxycrotonic acid.
Example 8
This example differs from example 1 in that the methylating agent used in step S3 of this example is methyl iodide, and the molar ratio of the reduction product to methyl iodide is 1: 3.5, methyl 4-methoxycrotonate is obtained in a yield of 85.5%, and the subsequent other steps refer to example 1 to obtain 4-methoxycrotonic acid.
Example 9
This example differs from example 1 in that the methylating agent used in step S3 of this example is methyl triflate, the molar ratio of the reduction product to the methyl triflate is 1: 3.5, methyl 4-methoxycrotonate is obtained in a yield of 83.6%, and the subsequent further steps refer to example 1 to obtain 4-methoxycrotonic acid.
Comparative example 1
A one-pot method for preparing high-purity trans-4-dimethylamino crotonate (CN 105669479A) adopts methyl crotonate as a starting material to perform bromination reaction with NBS in chloroform to obtain methyl 4-bromocrotonate. The starting material of this comparative example is highly toxic, costly, and the reaction conditions and intermediate products are highly allergenic.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The preparation method of the 4-methoxy crotonic acid is characterized by comprising the following steps:
after the reaction of glyoxylic acid and a phosphorus reagent, reducing aldehyde group, carrying out hydroxyl methylation and hydrolyzing to obtain 4-methoxy crotonic acid;
the phosphorus reagent includes a compound represented by the following general formula (1):
wherein R is1、R2、R3Independently are alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl.
2. The method of claim 1, comprising the steps of:
A. reacting glyoxylic acid with a phosphorus reagent under an alkaline condition to obtain an intermediate product;
B. reducing aldehyde groups of the intermediate product obtained in the step A into hydroxyl groups by using a reducing reagent to obtain a reducing product;
C. carrying out hydroxyl methylation on the reduction product obtained in the step B by using a methylating agent to obtain 4-methoxy methyl crotonate;
D. and D, carrying out alkaline hydrolysis on the methyl 4-methoxycrotonate obtained in the step C to obtain 4-methoxycrotonic acid.
3. The method according to claim 1 or 2, wherein the glyoxylic acid comprises glyoxylic acid monohydrate.
4. The method according to claim 3, wherein the molar ratio of the glyoxylic acid monohydrate to the phosphorus reagent is 1: 1-2;
preferably, the molar ratio of glyoxylic acid monohydrate to phosphorus reagent is 1: 1.2 to 1.5.
5. The method according to claim 2, wherein the alkali under alkaline conditions in step a comprises at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide.
6. The method according to claim 2, wherein the molar ratio of the intermediate product to the reducing agent in step B is 1: 0.5-2, preferably 1: 1 to 1.5, and more preferably 1: 1.3.
7. the method of claim 6, wherein the reducing agent comprises at least one of sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, zinc powder, palladium on carbon, and platinum, preferably zinc powder.
8. The method of claim 2, wherein the methylating agent in step C comprises at least one of methanol, methyl iodide, dimethyl sulfate and methyl trifluoromethanesulfonate.
9. The method of claim 2, wherein the base hydrolyzed in step D comprises at least one of lithium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
10. Use of a process according to any one of claims 1 to 9 in the synthesis of a medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210043110.0A CN114349631A (en) | 2022-01-14 | 2022-01-14 | Preparation method and application of 4-methoxy crotonic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210043110.0A CN114349631A (en) | 2022-01-14 | 2022-01-14 | Preparation method and application of 4-methoxy crotonic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114349631A true CN114349631A (en) | 2022-04-15 |
Family
ID=81092087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210043110.0A Pending CN114349631A (en) | 2022-01-14 | 2022-01-14 | Preparation method and application of 4-methoxy crotonic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114349631A (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB595174A (en) * | 1945-02-02 | 1947-11-27 | Shawinigan Chem Ltd | Purification of crotonic acid |
| GB626712A (en) * | 1946-08-14 | 1949-07-20 | Organon Labor Ltd | Preparation of crotonic acid derivatives and of phenanthrene derivatives therefrom |
| JPH0687784A (en) * | 1992-09-08 | 1994-03-29 | Daicel Chem Ind Ltd | Production of crotonic acid and crotonic acid derivative |
| JP2007084506A (en) * | 2005-09-26 | 2007-04-05 | Fujifilm Corp | Method for producing croconic acid compound |
| CN101003473A (en) * | 2007-01-12 | 2007-07-25 | 扬子石油化工股份有限公司 | Method for synthesizing crotonic acid by using byproduct of croton aldehyde |
| JP2010037206A (en) * | 2008-07-31 | 2010-02-18 | Kaneka Corp | Method for producing optically active o-methylserine or its salt |
| KR20100079285A (en) * | 2008-12-31 | 2010-07-08 | 코오롱생명과학 주식회사 | A method for preparing crotonic acid derivatives |
| CN102276462A (en) * | 2011-06-17 | 2011-12-14 | 华东师范大学 | Synthesis method of tert butyl crotonate |
| CN106278866A (en) * | 2016-07-21 | 2017-01-04 | 邯郸学院 | A kind of 2 alkyl replace .beta.-methylacrylic acid and the synthetic method of ester thereof |
| CN109608334A (en) * | 2019-01-11 | 2019-04-12 | 盐城通海生物科技有限公司 | A method of synthesis 4- methoxyl group ethyl crotonate |
-
2022
- 2022-01-14 CN CN202210043110.0A patent/CN114349631A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB595174A (en) * | 1945-02-02 | 1947-11-27 | Shawinigan Chem Ltd | Purification of crotonic acid |
| GB626712A (en) * | 1946-08-14 | 1949-07-20 | Organon Labor Ltd | Preparation of crotonic acid derivatives and of phenanthrene derivatives therefrom |
| JPH0687784A (en) * | 1992-09-08 | 1994-03-29 | Daicel Chem Ind Ltd | Production of crotonic acid and crotonic acid derivative |
| JP2007084506A (en) * | 2005-09-26 | 2007-04-05 | Fujifilm Corp | Method for producing croconic acid compound |
| CN101003473A (en) * | 2007-01-12 | 2007-07-25 | 扬子石油化工股份有限公司 | Method for synthesizing crotonic acid by using byproduct of croton aldehyde |
| JP2010037206A (en) * | 2008-07-31 | 2010-02-18 | Kaneka Corp | Method for producing optically active o-methylserine or its salt |
| KR20100079285A (en) * | 2008-12-31 | 2010-07-08 | 코오롱생명과학 주식회사 | A method for preparing crotonic acid derivatives |
| CN102276462A (en) * | 2011-06-17 | 2011-12-14 | 华东师范大学 | Synthesis method of tert butyl crotonate |
| CN106278866A (en) * | 2016-07-21 | 2017-01-04 | 邯郸学院 | A kind of 2 alkyl replace .beta.-methylacrylic acid and the synthetic method of ester thereof |
| CN109608334A (en) * | 2019-01-11 | 2019-04-12 | 盐城通海生物科技有限公司 | A method of synthesis 4- methoxyl group ethyl crotonate |
Non-Patent Citations (3)
| Title |
|---|
| JACQUELINE JIM ENEZ等: ""‘Syn-effect’ in the diastereoselective alkylation of 3-[(E)- a, b-unsaturated-g-substituted]-N-acyloxazolidinones"", 《TETRAHEDRON 》, vol. 71, pages 4590 - 4597, XP029231996, DOI: 10.1016/j.tet.2015.05.037 * |
| RESHMA KURANGI等: ""Synthesis and Anti-microbial studies of (E)-4-Oxoalk-2-enoic acids "", 《JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH 》, vol. 2, no. 4, pages 83 - 89 * |
| SAKUNCHAI KHUMSUBDEE等: ""Metathesis for catalyst design: metacatalysis"", 《TETRAHEDRON》, vol. 70, pages 1326 - 1335, XP028817724, DOI: 10.1016/j.tet.2013.12.040 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2230748C2 (en) | Method for preparing clarithromycin as crystals of form ii | |
| CN104710486A (en) | Method for synthesizing SGLT2 inhibitor drugs | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| CN107602651A (en) | A kind of preparation method of dehydroepiandros-sterone intermediate and dehydroepiandros-sterone | |
| CA2391145A1 (en) | Method of preparing clarithromycin | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| CN106749335B (en) | A kind of preparation method and application of halogenated oxygen cephalo-type intermediate | |
| CN113354574A (en) | Synthetic method of sodium picosulfate | |
| CN114349631A (en) | Preparation method and application of 4-methoxy crotonic acid | |
| CN102180914A (en) | Preparation method of 2-deoxidizing-D-glucose | |
| CN106977569B (en) | Preparation method of 6-methylene-17 α -hydroxyprogesterone acetate | |
| CN110498744B (en) | Preparation method of 1-ethyl-3-nitrobenzene | |
| CN115947759A (en) | Preparation method of medicine Ruidexiwei for treating new coronary disease | |
| CN109535210A (en) | A kind of method of synthesizing and purifying Tulathromycin impurity E | |
| CN106083971B (en) | A kind of preparation method of the acid of 5 β cholane of (E) 3 α hydroxyls 6 ethylidene, 7 ketone 24 | |
| CN101812108B (en) | Synthesis of hydrocortisone butyrate | |
| CN108707163B (en) | Preparation method of steviol glycoside | |
| CN114717280A (en) | Synthesis method of monopilavir | |
| CN108727445B (en) | Synthesis method of azithromycin impurity F | |
| CN109060473B (en) | Preparation method of ambroxol hydrochloride impurity reference substance | |
| EP1053244B1 (en) | Glycosidation of 4,5-epoxymorphinan-6-ols | |
| CN111944004A (en) | Preparation method of halometasone | |
| CN110804022A (en) | Preparation method of dexrazoxane | |
| CN111253434A (en) | Preparation method of dipalmitoyl phosphatidic acid | |
| CN106317064B (en) | The preparation method of methylnaltrexone bromide |
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 |