CN115340557A - Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine - Google Patents
Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine Download PDFInfo
- Publication number
- CN115340557A CN115340557A CN202211135765.7A CN202211135765A CN115340557A CN 115340557 A CN115340557 A CN 115340557A CN 202211135765 A CN202211135765 A CN 202211135765A CN 115340557 A CN115340557 A CN 115340557A
- Authority
- CN
- China
- Prior art keywords
- pyrrolo
- chloro
- pyrimidine
- iodo
- reaction
- 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
- CCVSDXKTRGSGEN-UHFFFAOYSA-N 4-chloro-5-iodo-7-methylpyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2N(C)C=C(I)C2=C1Cl CCVSDXKTRGSGEN-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims abstract description 20
- CBWBJFJMNBPWAL-UHFFFAOYSA-N 4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C(I)=CN2 CBWBJFJMNBPWAL-UHFFFAOYSA-N 0.000 claims abstract description 18
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 claims abstract description 13
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010189 synthetic method Methods 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000012153 distilled water Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 5
- 238000004537 pulping Methods 0.000 claims description 5
- CZMKXKXZBCESKA-UHFFFAOYSA-N 1,4-diazidobicyclo[2.2.2]octane Chemical compound N(=[N+]=[N-])C12CCC(CC1)(CC2)N=[N+]=[N-] CZMKXKXZBCESKA-UHFFFAOYSA-N 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000006192 iodination reaction Methods 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 125000002346 iodo group Chemical group I* 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
- 150000002391 heterocyclic compounds Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GCTFALKRTYVYFB-UHFFFAOYSA-N N1=CNC2=CC=NC2=C1Cl Chemical compound N1=CNC2=CC=NC2=C1Cl GCTFALKRTYVYFB-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which comprises the following steps of firstly, carrying out iodo reaction on 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and N-iodo succinimide to generate 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine; and then the 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine reacts with dimethyl carbonate under the action of alkali to generate 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine. The synthetic method is simple and convenient to operate, the raw materials are easy to obtain, and the reaction is mild.
Description
Technical Field
The invention belongs to the field of preparation of chemical drug intermediates, and particularly relates to a synthetic method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine.
Background
In recent years, heterocyclic compounds have received much attention for their wide application in medicinal chemistry research. Heterocyclic compounds are cyclic compounds containing at least two different elements as ring member atoms, the most common atoms including nitrogen, oxygen and sulfur. The heterocyclic compounds exist in a large amount in nature, and have important significance in our lives because of the existence of the heterocyclic compounds in various natural molecules such as hormones, antibiotics, caffeine and the like.
4-chloropyrrolopyrimidine is an intermediate of the drug tofacitinib used as drug substance in the treatment of adult patients with moderate to severe rheumatoid arthritis where methotrexate is poorly responsive or intolerant. The prior art for generating 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine by taking 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine as a raw material has the defects of long synthesis route, low yield, high raw material toxicity and environmental pollution.
Disclosure of Invention
Aiming at the technical problems, the invention provides a synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine. The synthetic method has the advantages of simple and convenient operation, easily obtained raw materials, mild reaction, feasible technology, reasonable economy and high cost performance.
The invention relates to a synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which comprises the steps of firstly carrying out iodination reaction on 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and N-iodosuccinimide to generate 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine; and then the 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine reacts with dimethyl carbonate under the action of alkali to generate 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine.
The reaction scheme is as follows:
the method specifically comprises the following steps:
step 1: adding DMF into a reaction bottle, adding 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine while stirring, then controlling the temperature below 10 ℃, slowly dropwise adding triethylamine, cooling to-5 to 5 ℃ after adding, adding N-iodosuccinimide, keeping the temperature for reacting for 30 minutes after adding, and monitoring by TLC until the reaction is finished; adding dichloromethane into the reaction solution, stirring for crystallization for 1 hour, performing suction filtration, pulping the filter cake with sodium thiosulfate aqueous solution, performing suction drying, washing with distilled water, performing suction drying, and drying to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine;
step 2: adding DMF into a reaction bottle, adding 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, dimethyl carbonate, potassium carbonate and 1, 4-diazido-bicyclo [2.2.2] octane under stirring, heating to 90-95 ℃ for reacting for 4 hours, and monitoring by TLC (thin layer chromatography) until the reaction is finished; cooling the reaction solution to room temperature, filtering to remove potassium carbonate, washing the filtrate with water, extracting the water layer with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, evaporating the organic layer, and drying to obtain 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine.
In step 1, the molar ratio of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine to N-iodosuccinimide and triethylamine is 1-1.5; the mass ratio of the methylene chloride to the methylene chloride is 1.
In the step 1, the mass concentration of the sodium thiosulfate aqueous solution is 10%.
In step 2, the molar ratio of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine to dimethyl carbonate, potassium carbonate and 1, 4-diazidobicyclo [2.2.2] octane is 1.5-2.
Compared with the existing synthetic process, the method has the advantages of short synthetic route, high yield and light environmental pollution, and can further extend the application of the compound in medicine research and development.
Drawings
FIG. 1 is a NMR spectrum of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine.
FIG. 2 is a NMR spectrum of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. These examples are for illustrative purposes only and should not be construed as specifically limiting the present invention.
Example 1:
the synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine in this example comprises the following steps:
1. synthesis of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine
Adding 40mL of DMF into a reaction bottle, adding 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (10g, 65.15mmol and 1.0eq) while stirring, then controlling the temperature to be below 10 ℃, slowly dropwise adding triethylamine (6.9g, 68.41mmol and 1.05eq), cooling to-5-5 ℃ after adding, adding N-iodo succinimide (17.5g, 78.18mmol and 1.2eq), preserving the temperature for reacting for 30 minutes after adding, and finishing the reaction when TLC monitors that the reaction is not carried out any more; adding dichloromethane 200mL, stirring for crystallization for 1 hour, performing suction filtration, pulping a filter cake by using 10% sodium thiosulfate aqueous solution 50mL, performing suction drying, washing by using distilled water 50mL, performing suction drying, and drying to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (15.4 g, yield is about 85%).
2. Synthesis of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine
Adding 50mL of DMF into a reaction bottle, and adding 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] under stirring]Pyrimidine (10g, 35.78mmol, 1.0eq), dimethyl carbonate (4.83g, 53.67mmol, 1.5eq), potassium carbonate (5.93g, 42.94mmol, 1.2eq), 1, 4-diazido-bicyclo [2.2.2] eq]Octane (0.8g, 7.16mmol, 0.2eq), heated to 90 ℃ for 4 hours, and the reaction was terminated when TLC monitored that the reaction did not proceed any more; cooling the reaction solution to room temperature, filtering to remove potassium carbonate, washing the filtrate with water (50 mLx 2), extracting the water layer with ethyl acetate (50 mLx 2), drying the organic layer with anhydrous sodium sulfate, evaporating the organic layer, and drying to obtain 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ]]Pyrimidine (9.45 g, yield about 90%). 1 H NMR(400MHz,CDCl 3 -d)δ:8.62(s,1H),7.35(s,1H),3.87(s,3H)。
Example 2:
the synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine in this example comprises the following steps:
1. synthesis of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine
Adding 40mL of DMF into a reaction bottle, adding 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (10g, 65.15mmol and 1.0eq) while stirring, then controlling the temperature to be below 10 ℃, slowly dropwise adding triethylamine (6.9g, 68.41mmol and 1.05eq), cooling to-5-5 ℃ after adding, adding N-iodo succinimide (17.5g, 78.18mmol and 1.2eq), preserving the temperature for 2 hours after adding, and finishing the reaction when TLC monitors that the reaction is not carried out any more; adding dichloromethane 200mL, stirring for crystallization for 1 hour, filtering, pulping the filter cake with 10% sodium thiosulfate aqueous solution 50mL, pumping, washing with distilled water 50mL, pumping, drying to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (13.11 g, yield: 72%).
2. Synthesis of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine
Adding 50mL of DMF into a reaction bottle, adding 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] under stirring]Pyrimidine (10g, 35.78mmol, 1.0eq), dimethyl carbonate (4.83g, 53.67mmol, 1.5eq), potassium carbonate (5.93g, 42.94mmol, 1.2eq), 1, 4-diazido bicyclo [2.2.2] eq]Octane (0.8g, 7.16mmol, 0.2eq), heated to 80 ℃ for 4 hours, and the reaction is finished when TLC monitors that the reaction is not carried out any more; cooling the reaction solution to room temperature, filtering to remove potassium carbonate, washing the filtrate with water (50 mLx 2), extracting the water layer with ethyl acetate (50 mLx 2), drying the organic layer with anhydrous sodium sulfate, evaporating the organic layer, and drying to obtain 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ]]Pyrimidine (8.2 g, yield about 78%). 1 H NMR(400MHz,CDCl 3 -d)δ:8.62(s,1H),7.35(s,1H),3.87(s,3H)。
Example 3:
the synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine in this example comprises the following steps:
1. synthesis of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine
Adding 40mL of DMF into a reaction bottle, adding 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (10g, 65.15mmol and 1.0eq) while stirring, then controlling the temperature to be below 10 ℃, slowly dropwise adding triethylamine (6.9g, 68.41mmol and 1.05eq), cooling to-5-5 ℃ after adding, adding N-iodo succinimide (17.5g, 78.18mmol and 1.2eq), preserving the temperature for reacting for 30 minutes after adding, and finishing the reaction when TLC monitors that the reaction is not carried out any more; adding dichloromethane 200mL, stirring for crystallization for 2 hours, carrying out suction filtration, pulping a filter cake by using 10% sodium thiosulfate aqueous solution 50mL, carrying out suction drying, washing by using distilled water 50mL, carrying out suction drying, and drying to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (15.84 g, the yield is about 87%).
2. Synthesis of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine
Adding 50mL of DMF into a reaction bottle, adding 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] under stirring]Pyrimidine (10g, 35.78mmol, 1.0eq), dimethyl carbonate (4.83g, 53.67mmol, 1.5eq), potassium carbonate (5.93g, 42.94mmol, 1.2eq), 1, 4-diazido-bicyclo [2.2.2] eq]Octane (0.8g, 7.16mmol, 0.2eq), heated to 100 ℃ for 4 hours, and the reaction is finished when TLC monitors that the reaction is not carried out any more; cooling the reaction solution to room temperature, filtering to remove potassium carbonate, washing the filtrate with water (50 mLx 2), extracting the aqueous layer with ethyl acetate (50 mLx 2), drying the organic layer with anhydrous sodium sulfate, evaporating the organic layer, and oven-drying to obtain 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ]]Pyrimidine (8.72 g, yield about 83%). 1 H NMR(400MHz,CDCl 3 -d)δ:8.62(s,1H),7.35(s,1H),3.87(s,3H)。
The present invention is illustrated by the above examples of the synthesis of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine of the present invention, but the present invention is not limited to the above examples, and it should be noted that modifications can be made by one of ordinary skill in the art without departing from the principles of the present invention, and such modifications are to be considered as within the scope of the present invention.
Claims (5)
1. A synthetic method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine is characterized by comprising the following steps:
firstly, 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and N-iodosuccinimide are subjected to iodination reaction to generate 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine; then 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine and dimethyl carbonate are subjected to methylation reaction under the action of alkali to generate 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine;
the reaction scheme is as follows:
2. the method of synthesis according to claim 1, characterized by comprising the steps of:
step 1: adding DMF into a reaction bottle, adding 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine under stirring, then controlling the temperature to be below 10 ℃, slowly dropwise adding triethylamine, cooling to-5 to 5 ℃ after adding, adding N-iodosuccinimide, keeping the temperature for reaction for 30 minutes after adding, and monitoring by TLC until the reaction is finished; adding dichloromethane into the reaction solution, stirring for crystallization for 1 hour, performing suction filtration, pulping the filter cake with sodium thiosulfate aqueous solution, performing suction drying, washing with distilled water, performing suction drying, and drying to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine;
step 2: adding DMF into a reaction bottle, adding 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine, dimethyl carbonate, potassium carbonate and 1, 4-diazido bicyclo [2.2.2] octane under stirring, heating to 90-95 ℃ for reacting for 4 hours, and monitoring by TLC until the reaction is finished; cooling the reaction solution to room temperature, filtering to remove potassium carbonate, washing the filtrate with water, extracting the water layer with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, evaporating the organic layer, and drying to obtain 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine.
3. The method of synthesis according to claim 2, characterized in that:
in step 1, the molar ratio of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine to N-iodosuccinimide and triethylamine is 1-1.5; the mass ratio of the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine to the dichloromethane is 1.
4. The method of synthesis according to claim 2, characterized in that:
in the step 1, the mass concentration of the sodium thiosulfate aqueous solution is 10%.
5. The method of synthesis according to claim 2, characterized in that:
in step 2, the molar ratio of 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine to dimethyl carbonate, potassium carbonate and 1, 4-diazidobicyclo [2.2.2] octane is 1.5-2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211135765.7A CN115340557A (en) | 2022-09-19 | 2022-09-19 | Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211135765.7A CN115340557A (en) | 2022-09-19 | 2022-09-19 | Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115340557A true CN115340557A (en) | 2022-11-15 |
Family
ID=83955325
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211135765.7A Pending CN115340557A (en) | 2022-09-19 | 2022-09-19 | Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115340557A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105431436A (en) * | 2013-05-14 | 2016-03-23 | 内尔维阿诺医学科学有限公司 | Pyrrolo[2,3-d]pyrimidine derivatives, process for their preparation and their use as kinase inhibitors |
| CN111454261A (en) * | 2020-05-27 | 2020-07-28 | 南京普锐达医药科技有限公司 | Synthesis method of 4-chloro-pyrrolopyrimidine compound |
| CN110036014B (en) * | 2016-12-28 | 2021-09-07 | 中国科学院上海药物研究所 | Compound with AXL inhibitory activity and preparation and application thereof |
-
2022
- 2022-09-19 CN CN202211135765.7A patent/CN115340557A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105431436A (en) * | 2013-05-14 | 2016-03-23 | 内尔维阿诺医学科学有限公司 | Pyrrolo[2,3-d]pyrimidine derivatives, process for their preparation and their use as kinase inhibitors |
| CN110036014B (en) * | 2016-12-28 | 2021-09-07 | 中国科学院上海药物研究所 | Compound with AXL inhibitory activity and preparation and application thereof |
| CN111454261A (en) * | 2020-05-27 | 2020-07-28 | 南京普锐达医药科技有限公司 | Synthesis method of 4-chloro-pyrrolopyrimidine compound |
Non-Patent Citations (3)
| Title |
|---|
| ANN CHRISTIN REIERSØLMOEN等: "Identification of fused pyrimidines as interleukin 17 secretion inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 155, pages 564 * |
| MICHAEL J. ZEILER等: "Second-Generation Meridianin Analogues Inhibit the Formation of Mycobacterium smegmatis Biofilms and Sensitize Polymyxin-Resistant Gram-Negative Bacteria to Colistin", 《CHEMMEDCHEM》, vol. 15, pages 1674 * |
| WEN-CHUNG SHIEH等: "Dual Nucleophilic Catalysis with DABCO for the N-Methylation of Indoles", 《J. ORG. CHEM.》, vol. 68, no. 5, pages 1955 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115340557A (en) | Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine | |
| SU1054352A1 (en) | N-glycosyl derivatives of daunorubicine having antibiotic effect | |
| JPH0670048B2 (en) | Decyanation of the pergolide intermediate | |
| CN101508679B (en) | Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid | |
| CN110804022B (en) | Preparation method of dexrazoxane | |
| CN101993464B (en) | Preparation method of capecitabine | |
| US2853495A (en) | Preparation of 2, 4-monofurfurylidene sorbitol | |
| CN111454261A (en) | Synthesis method of 4-chloro-pyrrolopyrimidine compound | |
| CN101935317B (en) | Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof | |
| CN106636239B (en) | Preparation method of chloramphenicol | |
| CA2508341A1 (en) | Processes for preparing quinolonecarboxylate derivatives | |
| CN110698523B (en) | Method for chemically synthesizing beta-arbutin | |
| HU195228B (en) | Process for producing new n-acetyl-neuraminic acid derivatives | |
| JPH01299294A (en) | 4,8-anhydro-n-acetyleuramic acid derivative | |
| JPH0372493A (en) | Production of 2'-o-substituted-adenosine-3',5'-cyclic phosphoric acid or its salt | |
| CN111533694A (en) | Synthetic method of 2-imido hydantoin compound | |
| US6723844B1 (en) | Preparation of K-252a | |
| CN115141234A (en) | Synthesis process of clindamycin phosphate raw material medicine | |
| SU1193152A1 (en) | Method of producing uracil derivatives | |
| CN104892709B (en) | A kind of method for synthesizing nelarabine | |
| JPS593476B2 (en) | Optically active chlorpheniramine/acylphenylglycine salt and method for producing the same | |
| CN103833751A (en) | Synthetic process of related impurity A of vinpocetine | |
| JPS6054361A (en) | Production of indole derivative | |
| HU177581B (en) | Process for producing amides of cyano-acetic acid derivatives of | |
| CN102464605B (en) | Preparation method of 4-nitro-piperidine derivative |
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 |