CN115947682A - Synthetic method of 3-bromo-2-hydroxy-6-methylpyridine - Google Patents
Synthetic method of 3-bromo-2-hydroxy-6-methylpyridine Download PDFInfo
- Publication number
- CN115947682A CN115947682A CN202310096613.9A CN202310096613A CN115947682A CN 115947682 A CN115947682 A CN 115947682A CN 202310096613 A CN202310096613 A CN 202310096613A CN 115947682 A CN115947682 A CN 115947682A
- Authority
- CN
- China
- Prior art keywords
- methylpyridine
- bromo
- hydroxy
- reaction
- reacting
- 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
- NYYSVYAQWWOZFG-UHFFFAOYSA-N 3-bromo-6-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(Br)C(=O)N1 NYYSVYAQWWOZFG-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 31
- UHMANLXCLQNQJD-UHFFFAOYSA-N 2-bromo-6-methylpyridin-3-ol Chemical compound CC1=CC=C(O)C(Br)=N1 UHMANLXCLQNQJD-UHFFFAOYSA-N 0.000 claims abstract description 28
- DHLUJPLHLZJUBW-UHFFFAOYSA-N 6-methylpyridin-3-ol Chemical compound CC1=CC=C(O)C=N1 DHLUJPLHLZJUBW-UHFFFAOYSA-N 0.000 claims abstract description 28
- BEAADMGNHFDPOM-UHFFFAOYSA-N 2,3-dibromo-6-methylpyridine Chemical compound CC1=CC=C(Br)C(Br)=N1 BEAADMGNHFDPOM-UHFFFAOYSA-N 0.000 claims abstract description 27
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 26
- KSFXMDCBPCLNCM-UHFFFAOYSA-N 3-bromo-2-methoxy-6-methylpyridine Chemical compound COC1=NC(C)=CC=C1Br KSFXMDCBPCLNCM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 10
- 230000031709 bromination Effects 0.000 claims abstract description 6
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 239000012074 organic phase Substances 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 32
- 239000005457 ice water Substances 0.000 claims description 30
- 239000011541 reaction mixture Substances 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 238000004809 thin layer chromatography Methods 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 235000002639 sodium chloride Nutrition 0.000 claims description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000006378 damage Effects 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- OYWOQIZXMYQEHI-UHFFFAOYSA-N 1,3-thiazinane-2,4,6-trione Chemical compound O=C1CC(=O)SC(=O)N1 OYWOQIZXMYQEHI-UHFFFAOYSA-N 0.000 claims description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 3
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 3
- ZPATUOFYXSBHMN-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [H+].[H+].[H+].[Br-].[Br-].[Br-].C1=CC=NC=C1 ZPATUOFYXSBHMN-UHFFFAOYSA-N 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 9
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 238000007792 addition Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- HQYNSFAFYFMRLG-UHFFFAOYSA-N tribromo phosphite Chemical compound BrOP(OBr)OBr HQYNSFAFYFMRLG-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KOBUELJRZDJHTE-UHFFFAOYSA-N 3,5-dibromo-6-methyl-1h-pyridin-2-one Chemical compound CC=1NC(=O)C(Br)=CC=1Br KOBUELJRZDJHTE-UHFFFAOYSA-N 0.000 description 1
- JEAVIRYCMBDJIU-UHFFFAOYSA-N 6-methyl-1h-pyridin-2-one Chemical compound CC1=CC=CC(O)=N1 JEAVIRYCMBDJIU-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method of 3-bromo-2-hydroxy-6-methylpyridine, which is characterized by comprising the following steps: 1) Reacting 3-hydroxy-6-methylpyridine with a bromization reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine; 2) Reacting 2-bromo-3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2, 3-dibromo-6-methylpyridine; 3) Reacting 2, 3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine; 4) The 3-bromo-2-methoxy-6-methylpyridine reacts with acid to remove methyl to obtain the 3-bromo-2-hydroxy-6-methylpyridine, and the method has the advantages of simple process line, mild reaction conditions, lower production cost, high yield and suitability for large-scale production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a synthetic method of 3-bromo-2-hydroxy-6-methylpyridine.
Background
3-bromo-2-hydroxy-6-methylpyridine has wide application as fine chemical raw materials, medical intermediates and the like: as reported in patent WO2015089192A1, it can synthesize lysine-specific demethylase-1 inhibitors useful for the treatment of cancers such as prostate, breast, bladder, lung, melanoma and the like. As reported in patent WO2008101682A2, the novel bactericide can be synthesized.
The synthesis process for 3-bromo-2-hydroxy-6-methylpyridine disclosed and reported at present uses 2-hydroxy-6-methylpyridine as a raw material, firstly reacts with a bromination reagent to obtain 3, 5-dibromo-6-methylpyridine-2-ol, the yield is 88%, then a bromine atom is selectively removed by n-butyl lithium under cryogenic conditions (-60 ℃ to-90 ℃) to obtain a crude product of 3-bromo-2-hydroxy-6-methylpyridine, and the final product needs to be purified by a column due to poor dehalogenation effect, and the yield is only 17%. (reference: WO2015089192A1 and WO2016037005A 1), the synthetic routes are shown in the following formula. The process is complicated, and the operation is unsafe due to the use of highly flammable n-butyllithium; in addition, a large amount of by-products are generated during regioselective debromination, so that the post-treatment of the final product is difficult, and pure 3-bromo-2-hydroxy-6-methylpyridine is difficult to obtain; the total yield is not high and is less than 15 percent, so that the industrialization cost is high; therefore, the process is not suitable for large-scale production.
In conclusion, the existing synthesis method of 3-bromo-2-hydroxy-6-methylpyridine has the problems of high industrial cost and unsuitability for large-scale production due to complex operation of technological processes, poor operation safety, low total yield and the like.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthesis method of 3-bromo-2-hydroxy-6-methylpyridine, which has the advantages of simple process route, mild reaction conditions, low production cost and high yield and is suitable for large-scale production.
The technical scheme adopted by the invention for solving the technical problems is as follows: a synthetic method of 3-bromo-2-hydroxy-6-methylpyridine comprises the following steps:
(1) Reacting 3-hydroxy-6-methylpyridine with a bromization reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine;
(2) Reacting 2-bromo-3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2, 3-dibromo-6-methylpyridine;
(3) Reacting 2, 3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine;
(4) 3-bromo-2-methoxy-6-methylpyridine reacts with acid to remove methyl to obtain 3-bromo-2-hydroxy-6-methylpyridine.
Further, the specific process of the step (1) is as follows: adding 3-hydroxy-6-methylpyridine into solvent pyridine, stirring for dissolving, slowly adding a bromization reagent at a temperature of between 5 ℃ below zero and T1 of less than or equal to 50 ℃, controlling the temperature at T2 of between 10 ℃ and T2 of less than or equal to 100 ℃, continuously reacting at the temperature T2 until the reaction is complete, carrying out TLC detection on the reaction raw materials, carrying out reduced pressure distillation on the reaction mixture after the reaction is complete, pouring residues into ice water, stirring for 1 hour at 0-5 ℃, forming a precipitate, filtering, washing the precipitate with water, and drying to obtain a light yellow solid 2-bromo-3-hydroxy-6-methylpyridine.
Further, the brominating reagent in the step (1) is bromine, pyridine tribromide, 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromosuccinimide or 1,3, 5-tribromo-1, 3, 5-thiazinane-2, 4, 6-trione; the mass ratio of the 3-hydroxy-6-methylpyridine to the brominating agent is 1: (1-3).
Further, the specific process of the step (2) is as follows: slowly adding a brominating reagent into 2-bromo-3-hydroxy-6-methylpyridine in the presence of a solvent, heating to T3 at the temperature of more than or equal to 20 ℃ and less than or equal to 150 ℃ after the adding is finished, reacting overnight, detecting by TLC (thin layer chromatography) the reaction is complete, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water for destruction, stirring for half an hour, adjusting the pH to 7-8 by using sodium bicarbonate solid, extracting by using an organic solvent for 3 times, combining organic phases, washing the organic phases by using saturated salt for twice, drying by using anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a light yellow liquid 2, 3-dibromo-6-methylpyridine.
Further, the brominating reagent in the step (2) is phosphorus oxybromide, phosphorus tribromide or trimethyl bromosilane; the mass ratio of the 2-bromo-3-hydroxy-6-methylpyridine to the brominating reagent is 1: (1-8).
Further, the solvent in the step (2) is acetonitrile, toluene, dichloroethane or 1, 4-dioxane; the organic solvent for extraction is ethyl acetate, dichloroethane, dichloromethane, toluene or methyl tert-butyl ether.
Further, the specific process of the step (3) is as follows: adding sodium methoxide into an organic solvent, then adding 2, 3-dibromo-6-methylpyridine, heating a reaction mixture to T4, wherein the temperature of T4 is more than or equal to 20 ℃ and less than or equal to 150 ℃, reacting overnight, the next day, cooling the reaction mixture to room temperature after TLC detection reaction is completed, then evaporating the solvent under reduced pressure, pouring residues into ice water, then extracting for 3 times by using dichloromethane, combining organic phases, washing the organic phases with saturated salt water twice, drying by anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain colorless liquid 3-bromo-2-methoxy-6-methylpyridine.
Further, the organic solvent in the step (3) is toluene, methanol, 1, 4-dioxane or N, N-dimethylformamide; the mass ratio of the 2, 3-dibromo-6-methylpyridine to the sodium methoxide is 1: (1-8).
Further, the specific process of the step (4) is as follows: slowly adding 3-bromo-2-methoxy-6-methylpyridine into an acid solution under stirring at normal temperature, heating the reaction mixture to T5, reacting at the temperature of more than or equal to 40 ℃ and less than or equal to 120 ℃, cooling the reaction mixture to room temperature after TLC detection reaction is completed, then evaporating the solvent under reduced pressure, pouring the residue into ice water, adjusting the pH of the residue to be =8 by using potassium carbonate solid, extracting by ethyl acetate for 3 times, combining organic phases, washing the organic phase with saturated common salt water twice, drying by anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain the white-like solid 3-bromo-2-hydroxy-6-methylpyridine.
Further, the acid solution in step (4) is hydrochloric acid, hydrobromic acid, acetic acid hydrogen bromide solution, dilute sulfuric acid or nitric acid.
Compared with the prior art, the invention has the advantages that: the invention discloses a synthesis method of 3-bromo-2-hydroxy-6-methylpyridine, which takes 3-hydroxy-6-methylpyridine as a raw material in a synthesis route and comprises 4 steps of synthesis of 2-bromo-3-hydroxy-6-methylpyridine, synthesis of 2, 3-dibromo-6-methylpyridine, synthesis of 3-bromo-2-methoxy-6-methylpyridine and synthesis of 3-bromo-2-hydroxy-6-methylpyridine. The preparation method has the advantages of cheap and easily-obtained raw materials, simple process, easy operation and low cost, and the product has higher yield and purity, is suitable for large-scale production and has wide application prospect.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 3-bromo-2-hydroxy-6-methylpyridine synthesized by the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A synthetic method of 3-bromo-2-hydroxy-6-methylpyridine comprises the following steps:
1) Reacting 3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine;
2) Reacting 2-bromo-3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2, 3-dibromo-6-methylpyridine;
3) Reacting 2, 3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine;
4) 3-bromo-2-methoxy-6-methylpyridine reacts with acid to remove methyl to obtain 3-bromo-2-hydroxy-6-methylpyridine, and the synthetic route is as follows:
the specific process of the step (1) is as follows: adding 3-hydroxy-6-methylpyridine into solvent pyridine, stirring for dissolving, slowly adding a bromization reagent at a temperature of between 5 ℃ below zero and T1 of less than or equal to 50 ℃, controlling the temperature at T2 of between 10 ℃ and T2 of less than or equal to 100 ℃, continuously reacting at the temperature T2 until the reaction is complete, carrying out TLC detection on the reaction raw materials, carrying out reduced pressure distillation on the reaction mixture after the reaction is complete, pouring residues into ice water, stirring for 1 hour at 0-5 ℃, forming a precipitate, filtering, washing the precipitate with water, and drying to obtain a light yellow solid 2-bromo-3-hydroxy-6-methylpyridine. Wherein the bromization reagent is bromine, pyridine tribromide, 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromosuccinimide or 1,3, 5-tribromo-1, 3, 5-thiazinane-2, 4, 6-trione; the mass ratio of 3-hydroxy-6-methylpyridine to brominating agent may be 1: (1-3).
The specific process of the step (2) is as follows: slowly adding a brominating reagent into 2-bromo-3-hydroxy-6-methylpyridine in the presence of a solvent, heating to T3 at the temperature of more than or equal to 20 ℃ and less than or equal to 150 ℃ after the adding is finished, reacting overnight, detecting by TLC (thin layer chromatography) the reaction is complete, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water for destruction, stirring for half an hour, adjusting the pH to 7-8 by using sodium bicarbonate solid, extracting by using an organic solvent for 3 times, combining organic phases, washing the organic phases by using saturated salt for twice, drying by using anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a light yellow liquid 2, 3-dibromo-6-methylpyridine. Wherein the brominating agent can be phosphorus oxybromide, phosphorus tribromide or trimethyl bromosilane; the mass ratio of 2-bromo-3-hydroxy-6-methylpyridine to brominating agent may be 1: (1-8). The solvent can be acetonitrile, toluene, dichloroethane or 1, 4-dioxane; the organic solvent for extraction may be ethyl acetate, dichloroethane, dichloromethane, toluene or methyl tert-butyl ether.
The specific process of the step (3) is as follows: adding sodium methoxide into an organic solvent, adding 2, 3-dibromo-6-methylpyridine, heating a reaction mixture to T4 at the temperature of more than or equal to 20 ℃ and less than or equal to 150 ℃, reacting overnight, detecting by TLC (thin layer chromatography) for the next day after the reaction is completed, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring residues into ice water, extracting by using dichloromethane for 3 times, combining organic phases, washing the organic phases with saturated salt twice, drying by using anhydrous sodium sulfate, and performing desolventization under reduced pressure to obtain colorless liquid 3-bromo-2-methoxy-6-methylpyridine. Wherein the organic solvent can be toluene, methanol, 1, 4-dioxane or N, N-dimethylformamide; the mass ratio of 2, 3-dibromo-6-methylpyridine to sodium methoxide may be 1: (1-8).
The specific process of the step (4) is as follows: slowly adding 3-bromo-2-methoxy-6-methylpyridine into an acid solution under stirring at normal temperature, heating the reaction mixture to T5, reacting at the temperature of more than or equal to 40 ℃ and less than or equal to 120 ℃, cooling the reaction mixture to room temperature after TLC detection reaction is completed, then evaporating the solvent under reduced pressure, pouring the residue into ice water, adjusting the pH of the residue to be =8 by using potassium carbonate solid, extracting by ethyl acetate for 3 times, combining organic phases, washing the organic phase with saturated common salt water twice, drying by anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain the white-like solid 3-bromo-2-hydroxy-6-methylpyridine. Wherein the acid solution can be hydrochloric acid, hydrobromic acid, acetic acid hydrogen bromide solution, dilute sulfuric acid or nitric acid.
Example 1
1. Synthesis of 2-bromo-3-hydroxy-6-methylpyridine
Adding 400mL of pyridine into a 1L four-mouth bottle, slowly adding 100g (916 mmol) of 3-hydroxy-6-methylpyridine under stirring, stirring and dissolving, cooling to 0 ℃ in an ice water bath, slowly dropwise adding 147g (916 mmol) of bromine, controlling the temperature to be not higher than 10 ℃, stirring and reacting at 0-10 ℃ for 1 hour, removing the ice water bath, and naturally heating to room temperature for reacting overnight. The next day, TLC detection of the reaction of the raw materials was complete, the reaction mixture was distilled under reduced pressure, the residue was poured into 800g of ice water, stirred at 0-5 ℃ for 1 hour to form a precipitate, filtered, washed with water and dried to obtain 152g of pale yellow solid 2-bromo-3-hydroxy-6-methylpyridine in 88% yield.
2. Synthesis of 2, 3-dibromo-6-methylpyridine
Acetonitrile (600 ml) is added into a 1L four-mouth bottle, 188g (1000 mmol) of 2-bromo-3-hydroxy-6-methylpyridine is added under the condition of normal temperature and stirring, then tribromooxyphosphorus (373g, 1301mmol) is slowly added, after the addition, the temperature is not obviously raised, the temperature is raised to 50 ℃, the reaction is kept overnight, next day, TLC detects the reaction is complete, the reaction liquid is cooled to the room temperature, then the reaction liquid is poured into 2kg of ice water to be destroyed, stirring is carried out for half an hour, the pH is adjusted to 7-8 by sodium bicarbonate solid, ethyl acetate is extracted (1L x 3), organic phases are combined, the organic phases are washed twice (1L x 2) by saturated salt water, anhydrous sodium sulfate is dried, decompression and desolventization is carried out, 234g of light yellow liquid 2, 3-dibromo-6-methylpyridine is obtained, and the yield is 93%.
3. Synthesis of 3-bromo-2-methoxy-6-methylpyridine
Adding 1.2L of 1, 4-dioxane into a 2L four-mouth bottle, adding 97g of sodium methoxide (1793 mmol) under stirring at normal temperature, then adding 150g of 2, 3-dibromo-6-methylpyridine (598 mmol), after the addition, heating the reaction mixture to 100 ℃, refluxing and reacting overnight, detecting the reaction by TLC for the next day, completely reacting, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into 1.5kg of ice water, then extracting by dichloromethane (1L x 3), combining organic phases, washing the organic phase twice by saturated saline (1L x 2), drying by anhydrous sodium sulfate, and removing the solution under reduced pressure to obtain 115g of colorless liquid 3-bromo-2-methoxy-6-methylpyridine with the yield of 95%.
4. Synthesis of 3-bromo-2-hydroxy-6-methylpyridine
Adding 1000mL of 30wt% hydrogen bromide acetic acid solution into a 2L four-mouth bottle, slowly adding 101g (500 mmol) of 3-bromo-2-methoxy-6-methylpyridine under stirring at normal temperature, heating the reaction mixture to 100 ℃ after the addition is finished, carrying out reflux reaction for 2 hours, detecting complete reaction by TLC, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into 1.2kg of ice water, adjusting the pH to =8 by using potassium carbonate solid, extracting (1L x 3) by using ethyl acetate, combining organic phases, washing the organic phases twice (1L x 2) by using saturated saline, drying by using anhydrous sodium sulfate, and carrying out desolventization under reduced pressure to obtain 88g of white-like solid 3-bromo-2-hydroxy-6-methylpyridine, wherein the yield is 93%. The 3-bromo-2-hydroxy-6-methylpyridine NMR spectrum is shown in FIG. 1, 1H NMR (400MHz, CDCI3): delta 2.35 (s, 3H), 5.97 (d, J =7.2Hz, 1H), 7.71 (d, J =7.2Hz, 1H), 12.36 (br.s, 1H).
Example 2
1. Synthesis of 2-bromo-3-hydroxy-6-methylpyridine 23003-35-2
Adding 400mL of pyridine into a 1L four-mouth bottle, slowly adding 100g (916 mmol) of 3-hydroxy-6-methylpyridine under stirring, stirring to dissolve, cooling to 10 ℃ in an ice water bath, then slowly dropwise adding 147g (916 mmol) of bromine, controlling the temperature to be not higher than 40 ℃, completing the dropwise addition, reacting at 40 ℃ for 5 hours, detecting by TLC that the raw materials are completely reacted, distilling the reaction mixture under reduced pressure, pouring the residue into 800g of ice water, stirring for 1 hour at 0-5 ℃, forming a precipitate, filtering, washing with water, and drying to obtain 131g of light yellow solid 2-bromo-3-hydroxy-6-methylpyridine, wherein the yield is 76%.
2. Synthesis of 2, 3-dibromo-6-methylpyridine
Acetonitrile (600 ml) is added into a 1L four-mouth bottle, 188g (1000 mmol) of 2-bromo-3-hydroxy-6-methylpyridine is added under stirring at normal temperature, then tribromooxyphosphorus (373g, 1301mmol) is slowly added, after the addition, obvious temperature rise is avoided, the temperature is raised to 80 ℃, the reaction is kept overnight, next day, TLC detection reaction is completed, the reaction liquid is cooled to room temperature, then the reaction liquid is poured into 2kg of ice water for destruction, stirring is carried out for half an hour, the pH value of sodium bicarbonate solid is adjusted to 7-8, ethyl acetate is extracted (1L. Multidot.3), organic phases are combined, the organic phase is washed twice (1L. Times.2) by saturated salt water, anhydrous sodium sulfate is dried, decompression and desolventization is carried out, 223g of light yellow liquid 2, 3-dibromo-6-methylpyridine is obtained, and the yield is 89%.
3. Synthesis of 3-bromo-2-methoxy-6-methylpyridine
Adding 1.2L of methanol into a 3L four-mouth bottle, adding 97g of sodium methoxide (1793 mmol) under an ice-water bath, then adding 150g of 2, 3-dibromo-6-methylpyridine (598 mmol), heating the reaction mixture to 70 ℃, carrying out reflux reaction overnight after the next day, detecting that the reaction is complete by TLC, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into 1.5kg of ice water, then extracting with dichloromethane (1L. X.3), combining organic phases, washing the organic phases twice with saturated saline (1L. Times.2), drying with anhydrous sodium sulfate, and carrying out desolventizing under reduced pressure to obtain 108g of colorless liquid 3-bromo-2-methoxy-6-methylpyridine, wherein the yield is 89%.
4. Synthesis of 3-bromo-2-hydroxy-6-methylpyridine
Adding 1000mL of 30wt% hydrobromic acid aqueous solution into a 2L four-mouth bottle, slowly adding 101g (500 mmol) of 3-bromo-2-methoxy-6-methylpyridine under stirring at normal temperature, after the addition is finished, heating the reaction mixture to 100 ℃ for reaction for 5 hours, detecting by TLC to complete the reaction, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into 1.2kg of ice water, adjusting the pH to =8 with potassium carbonate solid, extracting with ethyl acetate (1L x 3), combining organic phases, washing the organic phases twice with saturated saline (1L x 2), drying with anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain 83g of white-like solid 3-bromo-2-hydroxy-6-methylpyridine, with the yield of 88%.
Example 3
1. Synthesis of 2-bromo-3-hydroxy-6-methylpyridine
Adding 400mL of pyridine into a 1L four-mouth bottle, slowly adding 100g (916 mmol) of 3-hydroxy-6-methylpyridine under stirring, stirring for dissolving, cooling to 10 ℃ in an ice water bath, slowly adding 171g (960 mmol) of N-bromosuccinimide, controlling the temperature to be not higher than 20 ℃, stirring for reacting for 1 hour at 10-20 ℃, and reacting at 50 ℃ overnight. The next day, TLC detection of the reaction of the raw materials was complete, the reaction mixture was distilled under reduced pressure, the residue was poured into 800g of ice water, and after stirring at 0-5 ℃ for 1 hour, a precipitate was formed, which was filtered, washed with water, and dried to obtain 117g of 2-bromo-3-hydroxy-6-methylpyridine as a pale yellow solid with a yield of 68%.
2. Synthesis of 2, 3-dibromo-6-methylpyridine
Adding dichloroethane (600 ml) into a 1L four-mouth bottle, adding 188g (1000 mmol) of 2-bromo-3-hydroxy-6-methylpyridine under stirring at normal temperature, then slowly adding phosphorus tribromoxide (287g, 1000mmol), raising the temperature to 50 ℃ without obvious temperature after the addition, reacting overnight, detecting the reaction by TLC for the next day, completely reacting, cooling the reaction solution to room temperature, then pouring the reaction solution into 2kg of ice water for destruction, stirring for half an hour, adjusting the pH value of sodium bicarbonate solid to 7-8, extracting dichloroethane (1L x 3), combining organic phases, washing the organic phases twice (1L x 2) by using saturated salt water, drying by using anhydrous sodium sulfate, and performing decompression and desolventization to obtain 196g of pale yellow liquid 2, 3-dibromo-6-methylpyridine with the yield of 78%.
3. Synthesis of 3-bromo-2-methoxy-6-methylpyridine
Adding 1.2L of methanol into a 3L four-mouth bottle, adding 65g of sodium methoxide (1204 mmol) in an ice-water bath, then adding 150g of 2, 3-dibromo-6-methylpyridine (598 mmol), heating the reaction mixture to 68 ℃, carrying out reflux reaction overnight after the addition, detecting the reaction completion by TLC the next day, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into 1.5kg of ice water, then extracting with dichloromethane (1L. X.3), combining organic phases, washing the organic phases twice with saturated saline (1L. Times.2), drying with anhydrous sodium sulfate, and carrying out desolventization under reduced pressure to obtain 98g of colorless liquid 3-bromo-2-methoxy-6-methylpyridine with the yield of 81%.
4. Synthesis of 3-bromo-2-hydroxy-6-methylpyridine
Adding 1000mL of 30wt% hydrochloric acid into a 2L four-mouth bottle, slowly adding 101g (500 mmol) of 3-bromo-2-methoxy-6-methylpyridine under stirring at normal temperature, after the addition, heating the reaction mixture to 110 ℃ for reaction overnight, the next day, detecting by TLC that the reaction is complete, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into 1.2kg of ice water, adjusting the pH to =8 with potassium carbonate solid, extracting with ethyl acetate (1L x 3), combining organic phases, washing the organic phases twice with saturated saline (1L x 2), drying with anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain 76g of white-like solid 3-bromo-2-hydroxy-6-methylpyridine with the yield of 81%.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.
Claims (10)
1. A synthetic method of 3-bromo-2-hydroxy-6-methylpyridine is characterized by comprising the following steps:
(1) Reacting 3-hydroxy-6-methylpyridine with a bromization reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine;
(2) Reacting 2-bromo-3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2, 3-dibromo-6-methylpyridine;
(3) Reacting 2, 3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine;
(4) 3-bromo-2-methoxy-6-methylpyridine reacts with acid to remove methyl to obtain 3-bromo-2-hydroxy-6-methylpyridine.
2. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, wherein the specific process of step (1) is as follows: adding 3-hydroxy-6-methylpyridine into solvent pyridine, stirring for dissolving, slowly adding a bromization reagent at a temperature of between 5 ℃ below zero and T1 of less than or equal to 50 ℃, controlling the temperature at T2 of between 10 ℃ and T2 of less than or equal to 100 ℃, continuously reacting at the temperature T2 until the reaction is complete, carrying out TLC detection on the reaction raw materials, carrying out reduced pressure distillation on the reaction mixture after the reaction is complete, pouring residues into ice water, stirring for 1 hour at 0-5 ℃, forming a precipitate, filtering, washing the precipitate with water, and drying to obtain a light yellow solid 2-bromo-3-hydroxy-6-methylpyridine.
3. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 2, wherein: the brominating reagent in the step (1) is phosphorus oxybromide, phosphorus tribromide or trimethyl bromosilane; the mass ratio of the 3-hydroxy-6-methylpyridine to the brominating agent is 1: (1-3).
4. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, wherein the specific process of step (2) is as follows: slowly adding a brominating reagent into 2-bromo-3-hydroxy-6-methylpyridine in the presence of a solvent, heating to T3 at the temperature of more than or equal to 20 ℃ and less than or equal to 150 ℃ after the adding is finished, reacting overnight, detecting by TLC (thin layer chromatography) the reaction is complete, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water for destruction, stirring for half an hour, adjusting the pH to 7-8 by using sodium bicarbonate solid, extracting by using an organic solvent for 3 times, combining organic phases, washing the organic phases by using saturated salt for twice, drying by using anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a light yellow liquid 2, 3-dibromo-6-methylpyridine.
5. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 4, wherein: the brominating reagent in the step (2) is bromine, pyridine tribromide, 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromosuccinimide or 1,3, 5-tribromo-1, 3, 5-thiazine-2, 4, 6-trione; the mass ratio of the 2-bromo-3-hydroxy-6-methylpyridine to the brominating reagent is 1: (1-8).
6. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 4, wherein the method comprises the following steps: the solvent in the step (2) is acetonitrile, toluene, dichloroethane or 1, 4-dioxane; the organic solvent for extraction is ethyl acetate, dichloroethane, dichloromethane, toluene or methyl tert-butyl ether.
7. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, wherein the specific process of step (3) is as follows: adding sodium methoxide into an organic solvent, then adding 2, 3-dibromo-6-methylpyridine, heating a reaction mixture to T4, wherein the temperature of T4 is more than or equal to 20 ℃ and less than or equal to 150 ℃, reacting overnight, the next day, cooling the reaction mixture to room temperature after TLC detection reaction is completed, then evaporating the solvent under reduced pressure, pouring residues into ice water, then extracting for 3 times by using dichloromethane, combining organic phases, washing the organic phases with saturated salt water twice, drying by anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain colorless liquid 3-bromo-2-methoxy-6-methylpyridine.
8. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 7, wherein the method comprises the following steps: the organic solvent in the step (3) is toluene, methanol, 1, 4-dioxane or N, N-dimethylformamide; the mass ratio of the 2, 3-dibromo-6-methylpyridine to the sodium methoxide is 1: (1-8).
9. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, wherein the specific process of step (4) is as follows: slowly adding 3-bromo-2-methoxy-6-methylpyridine into an acid solution under stirring at normal temperature, heating the reaction mixture to T5, reacting at the temperature of more than or equal to 40 ℃ and less than or equal to 120 ℃, cooling the reaction mixture to room temperature after TLC detection reaction is completed, then evaporating the solvent under reduced pressure, pouring the residue into ice water, adjusting the pH of the residue to be =8 by using potassium carbonate solid, extracting by ethyl acetate for 3 times, combining organic phases, washing the organic phase with saturated common salt water twice, drying by anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain the white-like solid 3-bromo-2-hydroxy-6-methylpyridine.
10. The method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 9, wherein: the acid solution in the step (4) is hydrochloric acid, hydrobromic acid, acetic acid hydrogen bromide solution, dilute sulfuric acid or nitric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310096613.9A CN115947682A (en) | 2023-02-10 | 2023-02-10 | Synthetic method of 3-bromo-2-hydroxy-6-methylpyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310096613.9A CN115947682A (en) | 2023-02-10 | 2023-02-10 | Synthetic method of 3-bromo-2-hydroxy-6-methylpyridine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115947682A true CN115947682A (en) | 2023-04-11 |
Family
ID=87285991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310096613.9A Pending CN115947682A (en) | 2023-02-10 | 2023-02-10 | Synthetic method of 3-bromo-2-hydroxy-6-methylpyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115947682A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974175A (en) * | 2014-04-11 | 2015-10-14 | 天津药物研究院 | Preparation method of aminomethyl hydroxyisooxazole analogue |
| CN114656400A (en) * | 2022-04-26 | 2022-06-24 | 浙江科聚生物医药有限公司 | Preparation method of key intermediate of non-neferitone |
| WO2023011505A1 (en) * | 2021-08-06 | 2023-02-09 | 上海和誉生物医药科技有限公司 | Pyrimidine or pyridine derivative, preparation method therefor, and application thereof in pharmacy |
-
2023
- 2023-02-10 CN CN202310096613.9A patent/CN115947682A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974175A (en) * | 2014-04-11 | 2015-10-14 | 天津药物研究院 | Preparation method of aminomethyl hydroxyisooxazole analogue |
| WO2023011505A1 (en) * | 2021-08-06 | 2023-02-09 | 上海和誉生物医药科技有限公司 | Pyrimidine or pyridine derivative, preparation method therefor, and application thereof in pharmacy |
| CN114656400A (en) * | 2022-04-26 | 2022-06-24 | 浙江科聚生物医药有限公司 | Preparation method of key intermediate of non-neferitone |
Non-Patent Citations (2)
| Title |
|---|
| MEANA, ANGELA等: "Efficient regioselective preparation of monobromo- and bromoiodo-hydroxypyridines from dibromo derivatives via bromine-lithium exchange", 《SYNLETT》, vol. 11, 31 December 2003 (2003-12-31), pages 1678 - 1682 * |
| T. ROSS KELLY等: "Total Synthesis of Dimethyl Sulfomycinamate", 《TETRAHEDRON LETTERS》, vol. 36, no. 30, 31 December 1995 (1995-12-31), pages 5319 - 5322 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA3115570C (en) | Process for the preparation of a pde4 inhibitor | |
| CN114805314B (en) | Synthesis method of Entecavir | |
| CN111620869B (en) | Synthesis method of tert-butyl-1, 7-diazaspiro [3.5] nonane-1-formyloxy ester | |
| CN107936029B (en) | Method for synthesizing Ribociclib | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN114437031B (en) | Synthesis method of 6-methyl nicotine | |
| CN106977572A (en) | A kind of method using hyodesoxycholic acid as Material synthesis lithocholic acid | |
| CN103965280A (en) | Preparation method of fulvestrant intermediate | |
| CN108947884A (en) | A kind of Preparation Method And Their Intermediate of imrecoxib | |
| CN114539048B (en) | Carlong anhydride intermediate and preparation method of Carlong anhydride | |
| CN113248432A (en) | Novel method for preparing intermediate of roxasistat in high yield | |
| CN115947682A (en) | Synthetic method of 3-bromo-2-hydroxy-6-methylpyridine | |
| CN115417816B (en) | Preparation method of 3, 6-dibromo-1-chloro-isoquinoline | |
| CN107602339B (en) | Method for synthesizing 4-hydroxymethyl biphenyl | |
| CN104829588B (en) | A kind of Preparation Method And Their Intermediate of benzo [b] thiophene | |
| CN103755657B (en) | A kind of preparation method of Rivaroxaban intermediate | |
| CN109134187B (en) | A kind of technique for the bromobenzene synthesizing high steric hindrance | |
| CN108358866B (en) | Preparation method of febuxostat intermediate and application of febuxostat intermediate in preparation of febuxostat | |
| CN108558974B (en) | Preparation and application of sugar-derived nickel pyridine triazole catalyst | |
| CN106866608B (en) | A kind of preparation method of fluoro -3,4- dihydrocoumarin derivative | |
| CN112250586A (en) | Preparation method of terbutaline sulfate and B crystal form thereof | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN110283059A (en) | A kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method | |
| CN105801553B (en) | A kind of preparation method of Benzochromene derivatives | |
| CN112724089B (en) | Synthesis process of 2-amino-3-bromo-6-chloropyrazine |
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 |