CN115557842A - Preparation method of lenalidomide intermediate - Google Patents
Preparation method of lenalidomide intermediate Download PDFInfo
- Publication number
- CN115557842A CN115557842A CN202211151644.1A CN202211151644A CN115557842A CN 115557842 A CN115557842 A CN 115557842A CN 202211151644 A CN202211151644 A CN 202211151644A CN 115557842 A CN115557842 A CN 115557842A
- Authority
- CN
- China
- Prior art keywords
- mixture
- reaction
- lenalidomide
- blue light
- reactor
- 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.)
- Granted
Links
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960004942 lenalidomide Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000000203 mixture Substances 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- CRZGFIMLHZTLGT-UHFFFAOYSA-N methyl 2-methyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1C CRZGFIMLHZTLGT-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 26
- 238000002347 injection Methods 0.000 claims description 19
- 239000007924 injection Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 14
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052794 bromium Inorganic materials 0.000 abstract description 5
- 238000013032 photocatalytic reaction Methods 0.000 abstract description 3
- 238000011109 contamination Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000011259 mixed solution Substances 0.000 description 23
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 22
- 239000007788 liquid Substances 0.000 description 20
- 238000000605 extraction Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- FCGIVHSBEKGQMZ-UHFFFAOYSA-N methyl 2-(bromomethyl)-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1CBr FCGIVHSBEKGQMZ-UHFFFAOYSA-N 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 150000003254 radicals Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HHBCEKAWSILOOP-UHFFFAOYSA-N 1,3-dibromo-1,3,5-triazinane-2,4,6-trione Chemical compound BrN1C(=O)NC(=O)N(Br)C1=O HHBCEKAWSILOOP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- -1 however Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a lenalidomide intermediate, which comprises the following steps: dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture; and placing the mixture in a blue light environment for reaction to obtain a lenalidomide intermediate. The reaction formula of the mixture reaction is as follows:
wherein the content of the first and second substances,
is a lenalidomide intermediate; the solvent includes any one of acetonitrile and acetone. Dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture; and placing the mixture in a blue light environment for reaction, and obtaining a lenalidomide intermediate by using a photocatalytic reaction. The reaction is free from using environmentThe solvents causing contamination (bromine, carbon tetrachloride and methylene chloride), using acetonitrile or acetone as the solvent, have the advantage of being environmentally friendly.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a lenalidomide intermediate.
Background
Lenalidomide (Lenalidomide) is a commonly used drug for treating myelodysplastic syndrome, is first approved for sale in the united states in 2005 in 12 months, and is rapidly one of the best-selling anti-tumor drugs since the sale.
Wherein, the compound 2-bromomethyl-3-nitrobenzoic acid methyl ester is an important intermediate for synthesizing lenalidomide. In the synthesis of methyl 2-bromomethyl-3-nitrobenzoate, bromine (Br) is generally used 2 ) Carbon tetrachloride (CCl) 4 ) And dichloromethane (CH) 2 Cl 2 ) Is a solvent, however, bromine has strong oxidizing property and rancidity, carbon tetrachloride is highly toxic, methylene dichloride is anesthetic, and the environment is polluted, but the environment is difficult to treat without harm.
Disclosure of Invention
Therefore, a preparation method of the lenalidomide intermediate is needed, and the technical problem that the preparation method of the lenalidomide intermediate pollutes the environment in the prior art is solved.
In order to achieve the above purpose, the invention provides a technical scheme:
a method for preparing a lenalidomide intermediate, comprising the steps of:
dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture;
placing the mixture in a blue light environment for reaction to obtain the lenalidomide intermediate;
the reaction formula of the mixture reaction is as follows:
wherein, the first and the second end of the pipe are connected with each other,
is a lenalidomide intermediate;
the solvent includes any one of acetonitrile and acetone.
Preferably, the brominating agent includes any one of N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin.
Preferably, the mass ratio of the methyl 2-methyl-3-nitrobenzoate to the brominating agent is 1: (1-1.2).
Preferably, the solvent is acetonitrile.
Preferably, in the step of reacting the mixture by placing the mixture in a blue light environment, the reactor of the mixture is a coil reactor.
Preferably, the inner diameter of the coil reactor is 0.8 to 1.6mm, and the outer diameter of the coil reactor is 1.6 to 3.2mm.
Preferably, in the step of reacting the mixture in a blue light environment, the specific steps include:
injecting the mixture into the coil reactor through an injection pump, and placing the coil reactor in a blue light environment for reaction.
Preferably, the flow rate at which the mixture is injected into the coil reactor by an injection pump is in the range of 0.1 (mL/min) to 0.6 (mL/min).
Preferably, the flow rate at which the mixture is injected into the coil reactor by an injection pump is in the range of 0.1 (mL/min) to 0.15 (mL/min).
Preferably, the wavelength of the blue light is 400 to 480nm.
The preparation method of the lenalidomide intermediate provided by the embodiment of the invention has the following beneficial effects:
dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture; and placing the mixture in a blue light environment for reaction, and obtaining a lenalidomide intermediate by using a photocatalytic reaction. Solvents (bromine, carbon tetrachloride and dichloromethane) causing environmental pollution are not needed in the reaction, and acetonitrile or acetone is used as the solvent, so that the method has the advantage of environmental friendliness.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of methyl 2-bromomethyl-3-nitrobenzoate;
FIG. 2 is the NMR spectrum of methyl 2-bromomethyl-3-nitrobenzoate.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials and reagents used in the following examples, etc., are commercially available unless otherwise specified. In the quantitative tests in the following examples, three replicates were set, and the data are the mean value or the mean value ± standard deviation of the three replicates.
In addition, "and/or" in the whole text includes three schemes, taking a and/or B as an example, including a technical scheme, and a technical scheme that a and B meet simultaneously; in addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention.
In order to achieve the above purpose, the present invention provides a technical solution:
a preparation method of a lenalidomide intermediate comprises the following steps:
dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture;
placing the mixture in a blue light environment for reaction to obtain a lenalidomide intermediate;
the reaction formula of the mixture reaction is as follows:
wherein, the first and the second end of the pipe are connected with each other,
is 2-methyl-3-nitrobenzoic acid methyl ester;
the solvent includes any one of acetonitrile and acetone.
Specifically, the method comprises the steps of dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture; and placing the mixture in a blue light environment for reaction, and obtaining a lenalidomide intermediate by using a photocatalytic reaction. Solvents (bromine, carbon tetrachloride and dichloromethane) causing environmental pollution are not needed in the reaction, and acetonitrile or acetone is used as the solvent, so that the method has the advantage of environmental friendliness.
In some embodiments, the brominating agent comprises any one of N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin.
In some embodiments, the mass ratio of methyl 2-methyl-3-nitrobenzoate to brominating agent is 1: (1 to 1.2), preferably 1. Specifically, a slight excess of the brominating agent can promote the reaction, and a large excess of the brominating agent easily produces a dibromo-product.
In some embodiments, the solvent is acetonitrile. Specifically, the reaction which is more favorable for the mixture is a free radical substitution reaction, the bromination reagent has high solubility in acetonitrile, the generation of free radicals in the reaction is favorable, and in addition, the solubility of the lenalidomide intermediate generated by the reaction of the mixture in acetonitrile is high, so that the subsequent purification treatment of the lenalidomide intermediate is favorable.
In some embodiments, in the step of reacting the mixture by placing the mixture in a blue light environment, the reactor of the mixture is a coil reactor. More specifically, the method uses a coil reactor, uses a continuous flow preparation method to prepare the lenalidomide intermediate, and shortens the reaction time, wherein the reaction time of the mixture in the method is 5-30 min. The reaction time for preparing the lenalidomide intermediate (the compound 2-bromomethyl-3-nitrobenzoic acid methyl ester) is short, and the defect that the reaction time for preparing the compound 2-bromomethyl-3-nitrobenzoic acid methyl ester is more than 24 hours in the prior art is overcome.
In some embodiments, the coil reactor has an inner diameter of 0.8 to 1.6mm and an outer diameter of 1.6 to 3.2mm, preferably, the coil reactor has an inner diameter of 0.8mm and an outer diameter of 1.6mm.
In some embodiments, the step of reacting the mixture in a blue light environment comprises the following specific steps:
the mixture was injected into the coil reactor by means of an injection pump and the coil reactor was placed in a blue environment for the reaction.
In some embodiments, the mixture is injected into the coil reactor by an injection pump at a flow rate of 0.1 (mL/min) to 0.6 (mL/min).
In some embodiments, the flow rate of the mixture injected into the coil reactor by the syringe pump is 0.1 (mL/min) to 0.15 (mL/min), specifically, the smaller the flow rate, the higher the yield, but the longer the corresponding reaction time, and the flow rate of the reactor is set to 0.1 (mL/min) to 0.15 (mL/min) in the present invention, and the reaction time is controlled within 30min while ensuring the reaction yield.
In some embodiments, the blue light has a wavelength of 400 to 480nm, preferably, the blue light has a wavelength of 425nm.
The following are specific examples, and the starting materials in the examples are all commercially available products unless otherwise specified.
Example 1
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.6mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, keeping the blue light irradiation reactor for 5min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 45%.
Example 2
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.3mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, keeping the blue light irradiation reactor for 10min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 57%.
Example 3
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.15mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, standing for 20min, adding saturated sodium sulfite and ethyl acetate into effluent of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 78%.
Example 4
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, keeping the reaction time for 30min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 85%.
Example 5
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL of acetone, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, standing for 30min, adding saturated sodium sulfite and ethyl acetate into effluent of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 68%.
Example 6
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and 1, 3-dibromo-5, 5-dimethylhydantoin (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, keeping the residence time of 30min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as an internal nuclear magnetic standard, and calculating to obtain the nuclear magnetic yield of 43%.
Comparative example 1
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL tetrahydrofuran, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, standing for 30min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as an internal nuclear magnetic standard, and calculating to obtain the nuclear magnetic yield of 2%.
Comparative example 2
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mLN, N-dimethylformamide, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, keeping the reaction time for 30min, adding saturated sodium sulfite and ethyl acetate into effluent of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as an internal nuclear magnetic standard, and calculating to obtain the nuclear magnetic yield of 0%.
Comparative example 3
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-dibromo cyanoacetamide (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, keeping the blue light irradiation reactor for 30min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 0%.
Comparative example 4
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-trione (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, simultaneously opening a blue light irradiation reactor, allowing the mixed solution to stay for 30min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxy nuclear magnetic benzene as an internal standard, and calculating to obtain the yield of 43%.
Comparative example 5
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL acetonitrile, stirring for 10min to obtain a mixed solution, after a system is clarified, inputting the mixed solution into a coil reactor at the flow rate of 0.1mL/min through an injection pump, reacting for 30min, adding saturated sodium sulfite and ethyl acetate into effluent liquid of the coil reactor for extraction and liquid separation, taking an organic phase, performing vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 0%.
Comparative example 6
Respectively dissolving 2-methyl-3-nitrobenzoic acid methyl ester (2mmol, 1eq) and N-bromosuccinimide (2.2mmol, 1.1eq) in 4mL acetonitrile, placing the mixture in a reaction kettle, simultaneously turning on blue light for irradiation, reacting for 1h at room temperature, adding saturated sodium sulfite and ethyl acetate into reaction liquid for extraction and liquid separation, taking an organic phase for vacuum concentration, adding 1,3, 5-trimethoxybenzene as a nuclear magnetic internal standard, and calculating to obtain the nuclear magnetic yield of 85%.
As is clear from the experimental results of examples 1 to 6 and comparative examples 1 to 5, the solvent is preferably acetonitrile, the brominating solvent is preferably N-bromosuccinimide, and the flow rate of the syringe pump is preferably 0.1mL/min.
Referring to example 4 and comparative example 6, the reactor in example 4 is a coil reactor, and the yield after 30min is 85%, while the reactor in comparative example 6 is a reaction kettle, and the reaction kettle needs 1h of reaction to achieve 85%, so the reactor is selected as the coil reactor to be beneficial to accelerating the reaction rate compared with the traditional reaction kettle.
Referring to FIG. 1, the NMR spectrum of methyl 2-bromomethyl-3-nitrobenzoate is:
1H NMR(400MHz，Chloroform-d)δ8.10(dd，J＝7.9，1.4Hz，1H)，7.95(dd，J＝8.2，1.4Hz，1H)，7.53(t，J＝8.0Hz，1H)，5.15(s，2H)，3.99(s，3H).
referring to FIG. 2, the NMR spectrum of methyl 2-bromomethyl-3-nitrobenzoate is:
13C NMR(101MHz，Chloroform-d)δ165.96，150.64，134.81，132.73，132.43，129.22，127.92，53.18，22.84.
the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all equivalent structural changes made by using the contents of the present specification and the drawings, or any other related technical fields, which are directly or indirectly applied to the present invention, are included in the scope of the present invention.
Claims (10)
1. A preparation method of a lenalidomide intermediate is characterized by comprising the following steps:
dissolving 2-methyl-3-nitrobenzoic acid methyl ester and a bromization reagent in a solvent to obtain a mixture;
placing the mixture in a blue light environment for reaction to obtain the lenalidomide intermediate;
the reaction formula of the mixture reaction is as follows:
wherein the content of the first and second substances,
is a lenalidomide intermediate;
the solvent includes any one of acetonitrile and acetone.
2. A process for the preparation of a lenalidomide intermediate according to claim 1, wherein said brominating agent comprises any one of N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin.
3. A process for the preparation of a lenalidomide intermediate according to claim 1, wherein the mass ratio of methyl 2-methyl-3-nitrobenzoate to the brominating agent is 1: (1-1.2).
4. The process for the preparation of a lenalidomide intermediate according to claim 1, wherein said solvent is acetonitrile.
5. The method of claim 1, wherein the reactor of the mixture is a coil reactor in the step of subjecting the mixture to a blue light environment for reaction.
6. The method for preparing a lenalidomide intermediate according to claim 5, wherein the inner diameter of the coil reactor is 0.8 to 1.6mm, and the outer diameter of the coil reactor is 1.6 to 3.2mm.
7. The method for preparing lenalidomide intermediates according to claim 5, wherein the step of reacting the mixture in a blue light environment comprises the following specific steps:
injecting the mixture into the coil reactor through an injection pump, and placing the coil reactor in a blue light environment for reaction.
8. The method of preparing a lenalidomide intermediate according to claim 7, wherein the flow rate at which the mixture is injected into the coil reactor by an injection pump is from 0.1 (mL/min) to 0.6 (mL/min).
9. The method for preparing a lenalidomide intermediate according to claim 8, wherein the flow rate at which the mixture is injected into the coil reactor by an injection pump is from 0.1 (mL/min) to 0.15 (mL/min).
10. The method of preparing a lenalidomide intermediate according to claim 1, wherein the wavelength of the blue light is 400 to 480nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211151644.1A CN115557842B (en) | 2022-09-21 | 2022-09-21 | Preparation method of lenalidomide intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211151644.1A CN115557842B (en) | 2022-09-21 | 2022-09-21 | Preparation method of lenalidomide intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115557842A true CN115557842A (en) | 2023-01-03 |
| CN115557842B CN115557842B (en) | 2024-01-09 |
Family
ID=84741406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211151644.1A Active CN115557842B (en) | 2022-09-21 | 2022-09-21 | Preparation method of lenalidomide intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115557842B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218833A (en) * | 2016-12-15 | 2018-06-29 | 王琰萍 | A kind of preparation method of lenalidomide |
| US20180231561A1 (en) * | 2015-08-12 | 2018-08-16 | Celgene Corporation | Methods for treating solid tumors and the use of biomarkers as a predictor of clinical sensitivity to immunomodulatory therapies |
| CN110642834A (en) * | 2019-09-12 | 2020-01-03 | 天津瑞岭化工有限公司 | Method for synthesizing Lenalidomide |
-
2022
- 2022-09-21 CN CN202211151644.1A patent/CN115557842B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180231561A1 (en) * | 2015-08-12 | 2018-08-16 | Celgene Corporation | Methods for treating solid tumors and the use of biomarkers as a predictor of clinical sensitivity to immunomodulatory therapies |
| CN108218833A (en) * | 2016-12-15 | 2018-06-29 | 王琰萍 | A kind of preparation method of lenalidomide |
| CN110642834A (en) * | 2019-09-12 | 2020-01-03 | 天津瑞岭化工有限公司 | Method for synthesizing Lenalidomide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115557842B (en) | 2024-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ju et al. | The reaction of tertiary anilines with maleimides under visible light redox catalysis | |
| Lubineau | Water-promoted organic reactions: aldol reaction under neutral conditions | |
| Molteni et al. | Aqueous one-pot synthesis of pyrazoles, pyrimidines and isoxazoles promoted by microwave irradiation | |
| Wang et al. | Efficient copper-catalyzed synthesis of substituted pyrazoles at room temperature | |
| CN109320496B (en) | Selenocyanization reagent and preparation method and application thereof | |
| Brandão et al. | I2/NaH/DMF as oxidant trio for the synthesis of tryptanthrin from indigo or isatin | |
| Ozanne-Beaudenon et al. | Safe oxidation of sulfides into sulfoxides using SIBX | |
| Wang et al. | Silver-catalyzed decarboxylative C–H functionalization of cyclic aldimines with aliphatic carboxylic acids | |
| CN115557842A (en) | Preparation method of lenalidomide intermediate | |
| CN108586283B (en) | Method for preparing alpha-azidoketone compound based on photocatalysis | |
| Steiniger et al. | Olefination of carbonyls with alkenes enabled by electrophotocatalytic generation of distonic radical cations | |
| Holan et al. | Highly functionalized cyclopentane derivatives by tandem michael addition/radical cyclization/oxygenation reactions | |
| Miftyakhova et al. | Three-component synthesis of 5, 6-dihydropyrrolo [2, 1-a] isoquinolines from 1-aroyl-3, 4-dihydroisoquinolines, electron-deficient alkynes and NH-acids | |
| Ramapanicker et al. | An improved procedure for the synthesis of dehydroamino acids and dehydropeptides from the carbonate derivatives of serine and threonine using tetrabutylammonium fluoride | |
| Visweswara Sastry et al. | Copper‐Catalysed Tandem Synthesis of Substituted Quinazolines from Phenacyl Azides and O‐Carbonyl Anilines | |
| CN114014805B (en) | Preparation method of trifluoromethyl 2, 4-quinoline diketone compound | |
| CN110128345A (en) | A kind of preparation method of e derivatives | |
| DE2731259A1 (en) | PROCESS FOR THE MANUFACTURING OF SUBSTITUTED BENZALDEHYDE | |
| Chen et al. | Copper‐Promoted Tandem Radical Reaction of 2‐Oxindoles with Formamides: Facile Synthesis of Unsymmetrical Urea Derivatives | |
| Adam et al. | Photochemical and thermal denitrogenations of azoalkanes as mechanistic probes for the diradical intermediates involved in the di-. pi.-methane rearrangement of dibenzobarrelene | |
| CN108341761B (en) | Preparation method of organic selenium cyano compound | |
| CN109867284B (en) | Reagent capable of releasing carbon monoxide on site and preparation and application thereof | |
| CN113549051A (en) | Synthesis method of bisamide insecticide | |
| Chow et al. | Light-induced self-nitrosation of polycyclic phenols with nitrosamine. Excited state proton transfer | |
| Yin et al. | The synthesis of isoxazolo [2, 3-c] quinazolines via a cycloaddition of quinazoline-3-oxides and acrylates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |