CN116535402A - Method for preparing drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method - Google Patents
Method for preparing drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method Download PDFInfo
- Publication number
- CN116535402A CN116535402A CN202310439620.4A CN202310439620A CN116535402A CN 116535402 A CN116535402 A CN 116535402A CN 202310439620 A CN202310439620 A CN 202310439620A CN 116535402 A CN116535402 A CN 116535402A
- Authority
- CN
- China
- Prior art keywords
- reaction
- bromopyrazolo
- pyridine
- methyl ester
- carboxylic 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
- 238000000034 method Methods 0.000 title claims abstract description 42
- HCGDDQYSLHRKRM-UHFFFAOYSA-N methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate Chemical compound C1=C(Br)C=CC2=C(C(=O)OC)C=NN21 HCGDDQYSLHRKRM-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title claims abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000012065 filter cake Substances 0.000 claims abstract description 22
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- NIAATLPQSKGUBG-UHFFFAOYSA-N methyl 2-(5-bromopyridin-2-yl)acetate Chemical compound COC(=O)CC1=CC=C(Br)C=N1 NIAATLPQSKGUBG-UHFFFAOYSA-N 0.000 claims abstract description 13
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 239000007795 chemical reaction product Substances 0.000 claims abstract 2
- 238000004321 preservation Methods 0.000 claims description 18
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 2
- 238000004090 dissolution Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- -1 methyl N, N-dimethylformamide Chemical compound 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for preparing a drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by a one-pot method, belonging to the field of organic chemical synthesis, wherein the specific steps of the synthetic route of the invention are as follows: step one, adding methyl 2- (5-bromopyridin-2-yl) acetate, N-dimethylformamide dimethyl acetal and triethylamine into N, N-dimethylformamide, and stirring for reaction; step two, hydroxylamine-O-sulfonic acid is added into the reaction liquid of the step one, and the reaction is carried out at a constant temperature; step three, adding water to the reaction product obtained in the step two to separate out, recrystallizing a filter cake with methanol, and filtering and drying the filter cake; the 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester prepared by the method is simple in post-treatment, the obtained product is high in yield, high in purity and simple in process, separation and purification are not needed, the post-treatment operation is simple, the equipment requirements are low, the method is favorable for industrial production, the reaction system is environment-friendly, the used solvents are few in variety and quantity, the three wastes are less, the environmental pollution is avoided, and the method is favorable for industrial production and preparation of the product.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a method for preparing a drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by a one-pot method.
Background
The azacyclo drug block is one of structures with wide physiological activities, is often applied to the fields of medicines and pesticides, and often contains the azacyclo drug block in medicines for resisting bacteria, diminishing inflammation, relieving pain and treating and preventing mental diseases. The introduction of nitrogen heterocycles into drug molecules can improve the lipid solubility and water solubility of drugs, and the physiological activity, and many nitrogen heterocycles are one of the core structures for constructing pharmaceutically active molecules.
Methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate is a member of the family of blocks of drug molecules containing nitrogen heterocycles. German Mo Ci pharmaceutical Co-pending in patent (WO 2011015343) reports that small molecule drugs containing this fragment of methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate can be used for the treatment of neurological disorders. In patent WO2011015343, synlett,2017, vol.28, #13, p.1636-1640 and Bioorganic and Medicinal Chemistry Letters,2008, vol.18, #15, p.4388-4392, etc., the preparation routes of methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate are reported as follows:
the reaction steps of the route are longer, the post-treatment is complicated, the isomer exists in the final product, the purification is not good, the total yield is low, and the method is not suitable for industrial scale-up production. There is therefore a need to develop a new process for the preparation of methyl 6-bromopyrazolo [1,5-a ] pyridine-3-carboxylate as a pharmaceutical block.
Disclosure of Invention
The invention aims at overcoming the defects of the synthetic route of the 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester of the medicine building block, and provides a method for preparing the 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester of the medicine building block by adopting a one-pot method so as to solve the problems in the background art.
The invention relates to a method for preparing a drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester, which adopts the following synthetic route:
the method adopts 2- (5-bromopyridine-2-yl) methyl acetate as a raw material, N-dimethylformamide dimethyl acetal as a ring-forming reagent, triethylamine as a catalyst and hydroxylamine-O-sulfonic acid as an ammoniation reagent, and prepares the 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester with high yield and high purity by a one-pot method.
The method comprises the following operation steps: step one, adding methyl 2- (5-bromopyridin-2-yl) acetate, N-dimethylformamide dimethyl acetal and triethylamine into N, N-dimethylformamide, and stirring for reaction; step two, hydroxylamine-O-sulfonic acid is added into the reaction liquid; and thirdly, adding water to precipitate, recrystallizing a filter cake with methanol, and filtering and drying the filter cake.
Further, in the first step, the ratio of the amount of the methyl 2- (5-bromopyridin-2-yl) acetate to the amount of the N, N-dimethylformamide dimethyl acetal, triethylamine, hydroxylamine-O-sulfonic acid substance is 1: (1-10): (0.1-5): (1-15). Preferably 1 (1-5): (0.5-3): (1:10).
Further, in the first step, the volume ratio of the weight of the methyl 2- (5-bromopyridin-2-yl) acetate to the solvent N, N-dimethylformamide is 1: (1-50), preferably 1: (1-20).
Further, in the first step, the methyl 2- (5-bromopyridin-2-yl) acetate, N-dimethylformamide dimethyl acetal and triethylamine are added to N, N-dimethylformamide, and the reaction temperature is 50 to 130 ℃, preferably 70 to 100 ℃.
In the first step, methyl 2- (5-bromopyridin-2-yl) acetate and N, N-dimethylformamide dimethyl acetal and triethylamine are added into N, N-dimethylformamide, the temperature is preferably 70-100 ℃ during stirring reaction, and the reaction is kept for 1-5 hours; the reaction is preferably carried out for 3 to 5 hours.
Further, in the second step, the temperature is controlled to 70-90 ℃, preferably 75-85 ℃ after the hydroxylamine-O-sulfonic acid is added into the reaction solution.
In the second step, hydroxylamine-O-sulfonic acid is added into the reaction liquid and then the reaction is carried out for 3 to 7 hours in a heat preservation way.
In the third step, after the heat preservation reaction, the reaction system is slowly added into water, stirred for crystallization, cooled to 15-40 ℃, preferably 20-30 ℃, stirred for crystallization for 1-3 hours, and the filter cake is washed.
The invention has the beneficial effects that:
the invention successfully solves the problems of low yield, complex operation, multiple three wastes, isomer, difficult purification and the like existing in the existing synthetic preparation route of the methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate by a one-pot method. The preparation method has the advantages that the one-pot method is adopted to prepare the 6-bromopyrazolo [1,5-A ] pyridine-3-methyl carboxylate, the post-treatment is simple, the obtained product has high yield, high purity and simple process, separation and purification are not needed, the post-treatment operation is simple, the equipment requirement is low, the industrial production is facilitated, the reaction system is environment-friendly, the used solvents are few in variety and quantity, the three wastes are less, the environmental pollution is not caused, and the industrial production is facilitated to prepare the product.
Drawings
FIG. 1 is a nuclear magnetic spectrum of methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate prepared in example 1;
FIG. 2 is a high performance liquid chromatogram of methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate prepared in example 1.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention relates to a method for preparing a drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by a one-pot method, which comprises the following synthetic route:
the preparation method of the 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester comprises the following steps:
step one, adding methyl 2- (5-bromopyridin-2-yl) acetate, N-dimethylformamide dimethyl acetal and triethylamine into N, N-dimethylformamide, and stirring for reaction; step two, hydroxylamine-O-sulfonic acid is added into the reaction liquid; and thirdly, adding water to precipitate, recrystallizing a filter cake with methanol, and filtering and drying the filter cake.
Example 1
1000g (4.34 mol,1.0 eq) of methyl N, N-dimethylformamide 4L,2- (5-bromopyridin-2-yl) acetate, 1035g (8.7 mol,2 eq) of N, N-dimethylformamide dimethyl acetal, 440g (4.35 mol,1 eq) of triethylamine are added into a 10L three-necked flask, stirred and dissolved, the temperature is raised to 80 ℃ after the dissolution, the reaction is carried out for 3 hours under heat preservation, 737.6g (6.52 mol,1.5 eq) of hydroxylamine-O-sulfonic acid is added into the reaction liquid in batches after the end of the heat preservation, the reaction is carried out for 4 hours under heat preservation at 80 ℃, after the end of the heat preservation, 8L of water is slowly added into the reaction system after the end of the heat preservation, stirred and crystallized for 2 hours, 1L of water is used for washing the filter cake, 10L of methanol is used for recrystallizing the filter cake, the filter cake is filtered and dried, and the filter cake is dried under vacuum at 45 ℃ to obtain 1054.4g of light yellow solid 6-bromopyrazolo [1,5-A ]]Pyridine-3-carboxylic acid methyl ester with a yield of 95.1% and a purity of 99.4%. 1 H NMR(400MHz,CDCl 3 )δ8.68(s,1H),8.36(s,1H),8.07(d,J＝9.4Hz,1H),7.48(dd,J＝9.4,1.6Hz,1H),3.92(s,3H)。
The 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester prepared in the embodiment is characterized, and a nuclear magnetic spectrum and a high performance liquid chromatogram of the obtained 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester are respectively shown in figures 1 and 2.
Example 2
100g (414 mmol,1.0 eq) of methyl N, N-dimethylformamide 5L,2- (5-bromopyridin-2-yl) acetate, 518g (4.34 mol,10 eq) of N, N-dimethylformamide dimethyl acetal, 220g (2.17 mol,5 eq) of triethylamine are added into a 25L three-necked flask, stirred and dissolved, the temperature is raised to 130 ℃ after dissolution, the temperature is reduced to 90 ℃ after the completion of the heat preservation, 737.6g (6.51 mol,15 eq) of hydroxylamine-O-sulfonic acid is added into the reaction liquid in batches, the reaction is kept for 3 hours, the temperature is reduced to 15 ℃ after the completion of the heat preservation, 10L of water is slowly added into the reaction system, the mixture is stirred and crystallized for 1h,200ml of water is used for washing the filter cake, the filter cake is recrystallized by 1L of methanol, the filter cake is dried by filtration, and the light yellow solid 6-bromopyrazolo [1,5-A ] pyridine-3-methyl carboxylate with the yield of 92.5% and the purity of 99.1% is obtained by vacuum drying at 45 ℃.
Example 3
10g (43.4 mmol,1.0 eq) of methyl 2- (5-bromopyridin-2-yl) acetate (100 mL, N, N-dimethylformamide), 5.18g (43.4 mmol,1 eq) of dimethyl acetal (N, N-dimethylformamide) and 0.44g (4.34 mmol,0.1 eq) of triethylamine are added into a 500ml three-necked flask, stirred and dissolved, the temperature is raised to 50 ℃ after the dissolution, the temperature is raised to 70 ℃ after the completion of the heat preservation, 4.9g (43.4 mmol,1 eq) of hydroxylamine-O-sulfonic acid is added into the reaction liquid in batches, the temperature is raised to 7h after the completion of the heat preservation, the temperature is lowered to 40 ℃ after the completion of the heat preservation, 200ml of water is slowly added into the reaction system, the crystallized 3h,50ml of water is stirred to wash the filter cake, the filter cake is recrystallized with 100ml of methanol, the filter cake is dried by filtration, and the light yellow solid 6-bromopyrazolo [1,5-A ] pyridine-3-methyl carboxylate of 10g is obtained by vacuum drying at 45 ℃ to obtain a purity of 90.2%, 98.6%.
Example 4
100g (435 mmol,1.0 eq) of methyl 2- (5-bromopyridin-2-yl) acetate (400 ml) of N, N-dimethylformamide dimethyl acetal (77.6 g (650 mmol,1.5 eq) and triethylamine (21 mmol,0.5 eq) were added to a 2L three-necked flask, stirred and dissolved, the temperature was raised to 90 ℃ after dissolution, the reaction was allowed to stand for 4 hours, the temperature was lowered to 85 ℃ after the completion of the incubation, 98.4g (870 mmol,2 eq) of hydroxylamine-O-sulfonic acid was added to the reaction solution in portions, the reaction was allowed to stand for 5 hours, the temperature was lowered to 30 ℃ after the completion of the incubation, 800ml of water was slowly added to the reaction system, the cake was washed with 200ml of water under stirring, the cake was recrystallized with 1L of methanol, the cake was dried by filtration, and the cake was dried under vacuum at 45 ℃ to obtain 3.5g of methyl 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylate with a purity of 93.4%, 98.8%.
Example 5
1000g (4.34 mol,1.0 eq) of methyl N, N-dimethylformamide 20L,2- (5-bromopyridin-2-yl) acetate, 1552g (13.05 mol,3 eq) of N, N-dimethylformamide dimethyl acetal, 528g (5.21 mol,1.2 eq) of triethylamine are added into a 100L reaction kettle, stirred and dissolved, the temperature is raised to 100 ℃ after dissolution, the reaction is kept for 2 hours, the temperature is lowered to 75 ℃ after the end of the heat preservation, 1476g (13.05 mol,3 eq) of hydroxylamine-O-sulfonic acid is added into the reaction liquid in batches, the reaction is kept for 4 hours at 75 ℃ after the end of the heat preservation, 40L of water is slowly added into the reaction system after the end of the heat preservation, the mixture is stirred and crystallized for 2 hours, 1L of water is used for recrystallizing the filter cake, the filter cake is recrystallized by 10L of methanol, 1044.4g of pale yellow solid 6-bromopyrazolo [1,5-A ] pyridine-3-methyl carboxylate is obtained after the end of the heat preservation, and the vacuum drying is carried out at 45 ℃ to obtain the product with the purity of 94.2%, 99.3%.
The foregoing is merely a preferred embodiment of the invention, and it should be noted that modifications could be made by those skilled in the art without departing from the principles of the invention, which modifications would also be considered to be within the scope of the invention.
Claims (8)
1. A method for preparing a drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by a one-pot method is characterized by comprising the following synthetic route:
the synthetic route comprises the following specific steps:
step one, adding methyl 2- (5-bromopyridin-2-yl) acetate, N-dimethylformamide dimethyl acetal and triethylamine into N, N-dimethylformamide, and stirring for reaction;
step two, hydroxylamine-O-sulfonic acid is added into the reaction liquid of the step one, and the reaction is carried out at a constant temperature;
and thirdly, adding water to separate out the reaction product in the second step, recrystallizing the filter cake with methanol, and filtering and drying the filter cake.
2. The method for preparing the pharmaceutical block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by using the one-pot method according to claim 1, wherein the 2- (5-bromopyridin-2-yl) acetic acid methyl ester is used as a raw material; n, N-dimethylformamide dimethyl acetal is a ring-forming reagent; triethylamine is used as a catalyst, and hydroxylamine-O-sulfonic acid is used as an ammoniation reagent; the methyl 2- (5-bromopyridin-2-yl) acetate, N-dimethylformamide dimethyl acetal, triethylamine and hydroxylamine-O-sulfonic acid are used for preparing the 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by a one-pot method.
3. The method for preparing the pharmaceutical building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method according to claim 1, wherein the ratio of the amount of 2- (5-bromopyridin-2-yl) acetic acid methyl ester to the amount of N, N-dimethylformamide dimethyl acetal, triethylamine and hydroxylamine-O-sulfonic acid substance is 1: (1-10): (0.1-5):
(1-15)。
4. the method for preparing the pharmaceutical building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by using the one-pot method according to claim 1, wherein the volume ratio of the weight of the 2- (5-bromopyridin-2-yl) methyl acetate to the solvent N, N-dimethylformamide in the first step is 1: (1-50).
5. The method for preparing the pharmaceutical block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method according to claim 1, wherein the reaction temperature of the synthetic route is 50-130 ℃.
6. The method for preparing the pharmaceutical building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by using the one-pot method according to claim 1, wherein in the first step, 2- (5-bromopyridin-2-yl) methyl acetate, N-dimethylformamide dimethyl acetal and triethylamine are added into N, N-dimethylformamide, the stirring reaction is carried out at a temperature of preferably 70-100 ℃, and the reaction is carried out at a temperature of preferably 70-100 ℃ for 1-5h.
7. The method for preparing the pharmaceutical building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by using the one-pot method according to claim 1, wherein hydroxylamine-O-sulfonic acid in the second step is added into the reaction solution, then heated to 70-90 ℃, and subjected to heat preservation reaction for 3-7 hours.
8. The method for preparing the pharmaceutical building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by using the one-pot method according to claim 1 is characterized in that the reaction system is slowly added into water after the heat preservation reaction in the step three, stirred and crystallized, cooled to 15-40 ℃, stirred and crystallized for 1-3 hours, and a filter cake is washed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310439620.4A CN116535402A (en) | 2023-04-23 | 2023-04-23 | Method for preparing drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310439620.4A CN116535402A (en) | 2023-04-23 | 2023-04-23 | Method for preparing drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116535402A true CN116535402A (en) | 2023-08-04 |
Family
ID=87455308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310439620.4A Pending CN116535402A (en) | 2023-04-23 | 2023-04-23 | Method for preparing drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116535402A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471334A (en) * | 2009-08-05 | 2012-05-23 | 莫茨药物股份两合公司 | Metabotropic glutamate receptor modulators |
| CN107163043A (en) * | 2017-06-16 | 2017-09-15 | 上海毕得医药科技有限公司 | A kind of synthetic method of the carboxylic ester derivative of pyrazolo [1,5 a] pyridine 3 |
-
2023
- 2023-04-23 CN CN202310439620.4A patent/CN116535402A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471334A (en) * | 2009-08-05 | 2012-05-23 | 莫茨药物股份两合公司 | Metabotropic glutamate receptor modulators |
| CN107163043A (en) * | 2017-06-16 | 2017-09-15 | 上海毕得医药科技有限公司 | A kind of synthetic method of the carboxylic ester derivative of pyrazolo [1,5 a] pyridine 3 |
Non-Patent Citations (2)
| Title |
|---|
| KATRINA M. MENNIE ET AL.: "Divergent and Regioselective Synthesis of Pyrazolo[1, 5‑a]pyridines and Imidazo[1, 5‑a]pyridines", 《ORG. LETT.》, 31 December 2021 (2021-12-31), pages 4694 * |
| SHIVAJI S. PANDIT: "A NOVEL PYRAZOLO[1, 5-A]PYRIDINE DERIVATIVES WITH ARYL UREA, THIOUREA AND SULFONAMIDE MOIETIES: SYNTHESIS AND CYTOTOXICITY EVALUATIONS AGAINST MCF-7 CELL LINES", 《WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES》, 31 December 2018 (2018-12-31), pages 1192 - 1210 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110372713B (en) | Refining and purifying method of pranoprofen | |
| CN102925526A (en) | Preparation method for 6-amino penicillanic acid | |
| CN101914098B (en) | Preparation method of Meropenem trihydrate crystals | |
| CN114436924B (en) | Synthesis method of hydroxy pinacolone retinoic acid ester | |
| DE102019133627B3 (en) | CANNABIDIOL-3-SULFONIC ACID, PRODUCTION METHOD AND APPLICATION THEREOF AND CANNABIDIOL DERIVATIVE | |
| CN116535402A (en) | Method for preparing drug building block 6-bromopyrazolo [1,5-A ] pyridine-3-carboxylic acid methyl ester by one-pot method | |
| CN110240579B (en) | Polysubstituted gamma-butyrolactone compound, preparation method and application thereof | |
| CN102964336B (en) | Refining method of proton pump inhibitor and reducing method of N-oxide of proton pump inhibitor | |
| CN113816914B (en) | Preparation method of lorazepam intermediate | |
| CN110467600A (en) | A kind of De Lasha star meglumine salt crystal form L and preparation method thereof | |
| CN104628720A (en) | Refining method of moxifloxacin hydrochloride | |
| CN108546278A (en) | The process for purification of Mecobalamin | |
| CN112679570B (en) | Synthesis and purification method of tildipirosin | |
| CN111592553B (en) | Method for preparing moxidectin | |
| CN1332962C (en) | Method of synthesizing methanesulfonic acid parzhushaxing intermedinte | |
| CN113754715B (en) | Optical selective process synthesis method of (5R) -5-hydroxyl triptolide | |
| CN115433194B (en) | Synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| CN116199729A (en) | Crystal form B of acetamiprid and preparation method thereof | |
| CN104086552B (en) | A kind of process for purification of Penciclovir | |
| CN104163769A (en) | Preparation method of propionyl levocarnitine hydrochloride | |
| CN112724091B (en) | Method for industrially producing clobazam | |
| CN110684027B (en) | Application of dextro-fluoro-barnacamide and derivative thereof and preparation method of derivative | |
| CN110156805B (en) | Preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid | |
| CN112645964B (en) | Tyrosol-biotin small-molecule probe and preparation method and application thereof |
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 |