CN111196800B - Method for preparing lenalidomide - Google Patents
Method for preparing lenalidomide Download PDFInfo
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- CN111196800B CN111196800B CN201811378038.7A CN201811378038A CN111196800B CN 111196800 B CN111196800 B CN 111196800B CN 201811378038 A CN201811378038 A CN 201811378038A CN 111196800 B CN111196800 B CN 111196800B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a method for preparing lenalidomide. Specifically, the present invention provides a method for preparing lenalidomide comprising a nitro group reduction step, the nitro group reduction step comprising the steps of: in a first solvent, under the acidic condition and in the presence of a reducing agent and a catalyst, carrying out nitro reduction reaction on a compound of a formula II to obtain a compound of a formula I; wherein the catalyst is palladium carbon; the reducing agent is hypophosphorous acid or hypophosphite. The process has the advantages of high reaction yield, low production cost, environmental friendliness, and high implementation value and social and economic benefits.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of lenalidomide.
Background
Lenalidomide (3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione), a novel immunomodulator developed by Celgene corporation of America, was approved by FDA of America and marketed in 2006 for 1 month, is clinically mainly used for treating myelodysplastic syndrome (MDS) subtype with 5q deletion (5 th gap gene deletion of chromosome long arm) and multiple myeloma.
Lenalidomide (3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione), a thalidomide analog, is an immunomodulator with anti-angiogenic and anti-tumor properties, and has the following chemical structural formula:
the lenalidomide is prepared by a plurality of methods, wherein the formula (2008, 39, 888, china medical industry journal) adopts N-benzyloxycarbonyl-L-glutamine to be esterified by methanol, then is subjected to Pd/C catalytic deprotection to obtain L-glutamine methyl ester, the L-glutamine methyl ester is condensed with 2-bromomethyl-3-nitrobenzoic acid methyl ester to obtain an intermediate N- (4-nitro-1-oxo-1, 3-dihydro-2H-isoindol-2-yl) -L-glutamine methyl ester, the N- (4-amino-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) -L-glutamine methyl ester is obtained by Pd/C catalytic hydrogenation, and finally, the lenalidomide is obtained by intramolecular condensation, and the lenalidomide is shown in the following reaction formula. The method has the disadvantages of long steps and low total yield.
Muller et al in U.S. patent application US2006052609 and patent application documents: the reaction in CN97180299.8 adopts hydrogenation reaction under pressure, and is shown in the following reaction formula. The pressurization of the hydrogenation reaction greatly increases the risk of industrial operation.
In summary, there is an urgent need in the art to develop a method for preparing lenalidomide without using a hydrogenation reduction process, and the method has mild reaction conditions, high yield, high safety, and is suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of lenalidomide without adopting a hydrogenation reduction process, and the method has the advantages of mild reaction conditions, high yield and high safety, and is suitable for industrial production.
In a first aspect of the invention, there is provided a process for the preparation of lenalidomide, said process comprising a nitro-reduction step;
wherein the nitro group reduction step comprises the steps of:
carrying out nitro reduction reaction on a compound shown in a formula II (namely 3- (7-nitro-3-oxo-1H-isoindole-2-yl) piperidine-2, 6-diketone) in a first solvent under an acidic condition and in the presence of a reducing agent and a catalyst to obtain a compound shown in a formula I;
wherein the catalyst is palladium carbon; the reducing agent is hypophosphorous acid or hypophosphite.
In another preferred embodiment, the reducing agent is selected from: sodium hypophosphite, potassium hypophosphite, or combinations thereof.
In another preferred example, the reducing agent is sodium hypophosphite.
In another preferred embodiment, the acidic condition is pH <3.
In another preferred example, in the nitro reduction step, the acidic condition means that the nitro reduction reaction is performed in the presence of an acid, and the acid is selected from the group consisting of: phosphoric acid, hydrochloric acid, hypophosphorous acid (i.e., hypophosphorous acid), sulfuric acid, or combinations thereof.
In another preferred embodiment, the acid is selected from the group consisting of: phosphoric acid, hydrochloric acid, sulfuric acid, or a combination thereof.
In another preferred embodiment, in the nitro-reduction step, the first solvent is selected from the group consisting of: water, ethanol, methanol, or a combination thereof.
In another preferred example, the first solvent is water, ethanol aqueous solution or methanol aqueous solution; preferably, the first solvent is water.
In another preferred embodiment, the catalyst is 5% -10% palladium carbon.
In another preferred example, the reaction temperature of the nitro reduction reaction is 40-80 ℃, and/or the reaction time is 1-10 hours.
In another preferred example, the reaction temperature of the nitro reduction reaction is 50-80 ℃.
In another preferred example, the reaction time of the nitro group reduction reaction is 1.5 to 8 hours.
In another preferred example, the nitro reduction reaction is carried out under 0.5 to 2 atmospheric pressures; preferably, it is carried out under normal pressure.
In another preferred embodiment, in the nitro reduction step, the molar ratio of the reducing agent to the compound of formula II is (3 to 5): 1.
in another preferred embodiment, in the nitro reduction step, the amount of the catalyst is 1 to 10wt% of the compound of formula II.
In another preferred example, in the nitro group reduction step, the volume-to-mass ratio (ml/g) of the first solvent to the compound of formula II is (10-60): 1.
In another preferred embodiment, the volume-to-mass ratio (ml/g) of the first solvent to the compound of formula II is (10-30): 1.
In another preferred embodiment, when the acid is phosphoric acid, the molar ratio of the acid to the compound of formula II is (10 to 40): 1.
in another preferred example, the nitro reduction step further comprises, after the nitro reduction reaction is performed, the steps of: adding alkalizer to neutralize.
In another preferred embodiment, the alkalizing agent is selected from the group consisting of: ammonia, bicarbonate and/or carbonate.
In another preferred embodiment, the carbonate comprises: sodium carbonate, sodium bicarbonate and/or ammonium bicarbonate.
In another preferred embodiment, the neutralization is to a PH = 6.5-7.5.
In another preferred embodiment, the nitro group reduction step further comprises a first post-treatment step for isolating and/or purifying the compound of formula I.
In another preferred example, the first post-processing step includes: filtering, washing and/or drying steps.
In another preferred embodiment, the nitro group reduction step comprises:
(1) Adding a compound of formula II into a first solvent, and adding an acid, a reducing agent and a catalyst to perform a nitro reduction reaction to obtain a mixed system containing a salt of the compound of formula I;
(2) Adding an alkalizer into the mixed system containing the salt of the compound of the formula I obtained in the step (1) to obtain the mixed system containing the compound of the formula I; and
(3) And (3) separating and/or purifying the compound in the formula I from the mixed system containing the compound in the formula I obtained in the step (2) to obtain a purified compound in the formula I.
In another preferred embodiment, the process further comprises the step of preparing a compound of formula II:
wherein said step of preparing a compound of formula II comprises:
in a second solvent, in the presence of a weak base, a compound of formula A (2-bromomethyl-3-nitro-methyl benzoate) and a compound of formula B (3-aminopiperidine-2, 6-dione hydrochloride) are subjected to a condensation reaction to obtain a compound of formula II.
In another preferred embodiment, the second solvent is N, N-dimethylformamide, and/or the weak base is triethylamine.
In another preferred embodiment, the molar ratio of the compound of formula B to the compound of formula a is (1 to 1.5): 1.
in another preferred embodiment, the molar ratio of the weak base to the compound of formula a is (2 to 3): 1;
in another preferred embodiment, the volume-to-mass ratio (ml/g) of the second solvent to the compound of formula a is (5-15): 1.
in another preferred embodiment, the condensation reaction is carried out at a temperature of 50 to 80 ℃ (preferably, 80 ℃) and/or for a time of 2 to 10 hours; preferably, it is 2 to 6 hours.
In another preferred embodiment, the condensation reaction is carried out under an inert atmosphere, preferably under a nitrogen atmosphere.
In another preferred embodiment, said step of preparing the compound of formula II further comprises a second work-up step for isolating and/or purifying the compound of formula II.
In another preferred example, the second post-processing step includes: cooling, filtering, washing and/or drying.
In another preferred example, the washing is washing with water and/or alcohol (preferably, methanol, ethanol).
In another preferred example, the washing comprises: washing with water, and washing with alcohol (such as 95% ethanol).
In another preferred embodiment, the step of preparing the compound of formula II comprises the steps of:
(i) Dissolving a compound of a formula A in the second solvent, adding the weak base and a compound of a formula B into the second solvent in which the compound of the formula A is dissolved under stirring, and carrying out condensation reaction to obtain a mixed system containing a compound of a formula II;
(ii) (II) separating and/or purifying the compound of formula I from the mixed system comprising the compound of formula II obtained in step (I) to obtain a purified compound of formula I.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.
Detailed Description
The inventors have conducted extensive and intensive studies. In the process for preparing lenalidomide by 3- (7-nitro-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-diketone through nitro reduction, hypophosphorous acid or salts thereof (such as sodium hypophosphite) are used as a reducing agent for the nitro reduction for the first time, so that the high pressure required in the traditional hydrogenation reduction process is successfully avoided, and the reaction can be completed under normal pressure. The present invention has been accomplished based on this.
Definition of
As used herein, a hypophosphite salt may be a salt of hypophosphorous acid with any metal ion or ammonium, such as sodium hypophosphite, potassium hypophosphite, or ammonium hypophosphite, and the like, preferably, the hypophosphite salt is sodium hypophosphite.
Preparation method of lenalidomide
The invention provides a preparation method of neolenalidomide, which is used for carrying out nitro reduction on 3- (7-nitro-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-diketone (a compound shown in a formula II); wherein, the nitro reduction refers to obtaining the lenalidomide product by post treatment (such as neutralization, washing and the like) under the action of palladium carbon and hypophosphite (or acid thereof) in an acid system. Furthermore, in the process for the preparation of lenalidomide according to the present invention, the compound of formula II can be obtained by condensation reaction of 3-aminopiperidine-2, 6-dione hydrochloride (compound of formula a) with 2-bromomethyl-3-nitro-benzoic acid methyl ester (compound of formula B) under weak base conditions. Preferably, the reaction solution after the condensation reaction is cooled to room temperature, added into water and stirred, and the filter cake obtained by filtering is sequentially rinsed with water and an alcohol reagent and dried to obtain the compound of formula II.
Typically, the reaction scheme in the process for preparing lenalidomide of the present invention is as follows:
specifically, the method for preparing lenalidomide comprises the following steps:
alternative 1) a step of preparing a compound of formula II;
typically, the step of preparing the compound of formula II comprises: in a second solvent, in the presence of a weak base, carrying out condensation reaction on 3-aminopiperidine-2, 6-diketone hydrochloride (a compound shown in a formula A) and 2-bromomethyl-3-nitro-methyl benzoate (a compound shown in a formula B) to obtain 3- (7-nitro-3-oxo-1H-isoindole-2-yl) piperidine-2, 6-diketone (a compound shown in a formula II); and
2) A nitro reduction step for preparing lenalidomide from a compound of formula II: in a first solvent, under the acidic condition, in the presence of a catalyst (such as palladium carbon) and a reducing agent, the compound of the formula II is subjected to nitro reduction reaction, so that lenalidomide, namely the compound of the formula I, is obtained.
In another preferred example, in step 1), the second solvent is N, N-dimethylformamide, and/or the weak base is triethylamine.
In another preferred embodiment, in step 2), the compound of formula II is subjected to nitro reduction to obtain a solution containing lenalidomide salt (i.e., the salt of the compound of formula I), and then neutralized with a base, and separated (e.g., separated by filtration) to obtain lenalidomide.
In another preferred example, in the step 2), the catalyst is 5% -10% palladium carbon, and/or the first solvent is one or a mixture of water, ethanol and methanol; the preferred scheme is that water is used as a solvent.
In another preferred example, in the step 2), the acidic condition is realized by adding an acid into the first solvent, and the acid is one of phosphoric acid, hydrochloric acid and hypophosphorous acid; the reducing agent is a hypophosphite (such as sodium hypophosphite) or an acid thereof; and/or the alkalizer is ammonia water, bicarbonate and carbonate, and the carbonate comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and/or ammonium bicarbonate.
In another preferred embodiment, the reaction temperature in step 1) and/or step 2) is 50 to 80 ℃.
The main advantages of the invention include:
(a) The method has the advantages of mild process conditions (reaction under normal pressure), short reaction steps and simple operation;
(b) The method has the advantages of high reaction yield, low production cost, high safety, environmental friendliness, and high implementation value and social and economic benefits.
(c) The preparation method is simple and convenient in preparation process and is suitable for industrial production.
(d) The lenalidomide obtained by the method has high purity.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
EXAMPLE 1 preparation of 3- (7-Nitro-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione (Compound of formula II)
100g (0.61 mol) of 3-aminopiperidine-2, 6-dione hydrochloride (compound of formula A) are dissolved in 1000mL of DMF, stirred at room temperature, and 186g of (A), (B) and (C) are added0.76 mol) of 2-bromomethyl-3-nitro-benzoic acid methyl ester (compound of formula B) and 200mL of triethylamine, stirring at room temperature and nitrogen blanketing. Heating to 80 ℃, stirring for 4 hours, pouring the reaction solution into 3000mL of water, stirring, cooling to room temperature, and filtering; washing the filter cake with 5000mL of water, and pumping to dry; adding the filtered solid into 500mL 95% ethanol, pulping for 2 hours at room temperature, filtering, draining, and putting into an oven to be dried to obtain 151g (0.52 mol) of gray solid, wherein the yield is as follows: 85.6%, purity: 95.87 percent. ESI-MS (m/z) 290.0[ m ] +1] + .1H NMR(400MHz,DMSO-d6):11.05(s,1H),8.48(d,J＝8.4Hz,1H),8.20(d,J＝7.6Hz,1H),7.84(t,J＝8.0Hz,1H),5.21-5.16(m,1H),4.93-4.77(m,2H),2.93-2.87(m,1H),2.63-2.52(m,2H),2.04-2.01(m,1H)。
EXAMPLE 2 preparation of lenalidomide 3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione (Compound of formula I)
50g (0.173 mol) of 3- (7-nitro-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione is added into 600mL of water, 174g (1.81 mol) of phosphoric acid, 54.8g (0.52 mol) of sodium hypophosphite and 5g of 10% palladium carbon are added, the mixture is heated to 60 ℃ and stirred for two hours, the mixture is filtered while hot, ammonium bicarbonate is added into the filtrate to neutralize the pH value to be 7, the filtrate is filtered, washed by water and drained, and 43.06g (0.166 mol) of light yellow solid dried in an oven is put into the oven, the yield is as follows: 95.95 percent and the purity is 99.42 percent. ESI-MS (m/z) 260.0[ 2 ], [ M ] +1] + .1H NMR(400MHz,DMSO-d6):10.99(s,1H),7.18(t,J＝7.6Hz,1H),6.91(d,J＝6.8Hz,1H),6.79-6.77(m,1H),5.42(s,2H),5.12-5.07(m,1H),4.21-4.06(m,2H),2.95-2.86(m,1H),2.62-2.57(m,1H),2.34-2.04(m,1H),2.03-1.99(m,1H)。
EXAMPLE 3 preparation of lenalidomide 3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione
3- (7-Nitro-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione 1.45g (0.0050 mol) was added to 40mL of water and 40mL of methanol, 0.6mL (0.0071 mol) of hydrochloric acid, 2.65g (0.025 mol) of sodium hypophosphite, 145mg of 10% palladium on carbon, heated to 50 ℃ and stirred for 6 hours, filtered while hot, the filtrate was neutralized with sodium bicarbonate to pH 7, filtered, washed with water, drained, and put into an oven-dried pale yellow solid 1.11g (0.00428 mol), yield: 85.7 percent and 100 percent of purity.
Example 4 preparation of lenalidomide 3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione
2.9g (0.01 mol) of 3- (7-nitro-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione are added to 20mL (0.18 mol) of 50% hypophosphorous acid aqueous solution, 290mg of 10% palladium on carbon, heated to 50 ℃ and stirred for 6 hours, filtered while hot, the filtrate is neutralized to pH 7 with sodium bicarbonate, filtered, washed with water, drained, and placed in an oven-dried pale yellow solid 2.0g (0.00772 mol), yield: 77.22 percent and the purity is 94.62 percent.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (9)
1. A process for the preparation of lenalidomide, wherein said process comprises a nitro group reduction step;
wherein the nitro group reduction step comprises the steps of:
in a first solvent, under the acidic condition and in the presence of a reducing agent and a catalyst, carrying out nitro reduction reaction on a compound of a formula II to obtain a compound of a formula I; wherein the acidic condition refers to the nitro reduction reaction in the presence of acid, and the acid is phosphoric acid;
wherein the catalyst is 5-10% palladium carbon; the reducing agent is hypophosphite;
the first solvent is water;
the acidic condition refers to PH <3;
the reaction time is 2 to 6 hours.
2. The method of claim 1, wherein the reducing agent is selected from the group consisting of: sodium hypophosphite, potassium hypophosphite, or combinations thereof.
3. The method of claim 1,
the reaction time is 2 hours;
the reducing agent is selected from: sodium hypophosphite, potassium hypophosphite, or a combination thereof;
in the step of nitro reduction, the first solvent is water;
in the nitro reduction step, the acidic condition refers to that nitro reduction reaction is carried out in the presence of acid, and the acid is phosphoric acid; and
the molar ratio of the reducing agent to the compound of formula II is (3-5): 1 and the molar ratio of the acid to the compound of formula II is (10 to 40) when the acid is phosphoric acid.
4. The method of claim 1, wherein the nitro group reduction reaction is carried out at a reaction temperature of 40 to 80 ℃.
5. The method of claim 1, wherein the nitro group reduction step has one or more of the following characteristics:
the molar ratio of the reducing agent to the compound of formula II is (3-5): 1;
the dosage of the catalyst is 1 to 10 weight percent of the compound shown in the formula II; and/or
The volume-to-mass ratio (ml/g) of the first solvent to the compound of the formula II is (10-60): 1.
6. The method of claim 1, wherein the nitro-reduction step, after the nitro-reduction step, further comprises the steps of: adding alkalizer to neutralize.
7. The method of claim 1, further comprising the step of preparing a compound of formula II:
wherein the step of preparing the compound of formula II comprises:
in a second solvent, in the presence of weak base, the compound of formula B, i.e. 2-bromomethyl-3-nitro-benzoic acid methyl ester, and the compound of formula A, i.e. 3-aminopiperidine-2, 6-dione hydrochloride, are subjected to condensation reaction to obtain the compound of formula II.
8. The process of claim 7, wherein the second solvent is N, N-dimethylformamide and/or the weak base is triethylamine.
9. The method of claim 7, wherein the method has one or more of the following features:
the molar ratio of the compound of formula B to the compound of formula A is (1-1.5): 1;
the molar ratio of the weak base to the compound of the formula A is (2-3): 1;
the volume-to-mass ratio (ml/g) of the second solvent to the compound of formula A is (5-15): 1.
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| US6455801B1 (en) * | 1999-03-25 | 2002-09-24 | Arplas Projects Bv | Method and device for manufacturing a projection weld connection for plate material |
| WO2010100476A2 (en) * | 2009-03-02 | 2010-09-10 | Generics [Uk] Limited | Improved process |
| WO2011027326A1 (en) * | 2009-09-03 | 2011-03-10 | Ranbaxy Laboratories Limited | Process for the preparation of lenalidomide |
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- 2018-11-19 CN CN201811378038.7A patent/CN111196800B/en active Active
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| US6455801B1 (en) * | 1999-03-25 | 2002-09-24 | Arplas Projects Bv | Method and device for manufacturing a projection weld connection for plate material |
| WO2010100476A2 (en) * | 2009-03-02 | 2010-09-10 | Generics [Uk] Limited | Improved process |
| WO2011027326A1 (en) * | 2009-09-03 | 2011-03-10 | Ranbaxy Laboratories Limited | Process for the preparation of lenalidomide |
| CN104710405A (en) * | 2013-12-13 | 2015-06-17 | 江苏豪森药业股份有限公司 | 3-(4-amino-1, 3-dihydro-1-oxo-2 H-isoindole-2-yl)-2, 6-piperidinedione preparation method |
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