CN1321975C - Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use - Google Patents
Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use Download PDFInfo
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Abstract
The present invention relates to a new compound of 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate, preparation thereof and application. The compound has a chemical formula as shown in the formula (IV), and the compound (IV) is obtained by 4-(4-oxo-butyl) benzoyl-L-glutamate as a raw material which reacts with a bromating reagent in a C1 to C4 halogenated hydrocarbon solvent at the temperature of 20 DEG C to 30 DEG C under the protection of inert gas. The compound (IV) is an important midbody for synthesizing new medicine pemetrexed disodium for resisting tumors, and the compound develops a new way for synthesizing the pemetrexed disodium. Compared with the prior art, the synthesis way shortens reaction steps, reduces production cost, and is a method which is suitable for large-scale industrial production.
Description
(1) technical field
The present invention relates to a kind of new compound 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester, and its production and application.
(2) background technology
Pemetrexed (pemetrexed, have another name called LY231514, trade(brand)name Alimta) be a kind of novel anti folic acid antimetabolite, action target spot comprises pyrimidine and the purine how sharp enzyme in synthetic, so have another name called many targets antifol (multi2targeted antifolate, MTA).Demonstrating anti-tumor activity widely in external and clinical trial, is an antitumor drug that has potentiality.
Pemetrexed is to come scientist doctor Shi Quan of Chinese origin of company to unite Princeton university chemistry system through the research and development success in 10 years by gift.Nineteen nineties has many pieces of patents and document to introduce the chemical synthesis process of pemetrexed and disodium salt thereof, as Taylor.E.C. so far successively; Kuhnt.D.; Shih, C.; Etc.J.Med.Chem.1992,35,4450; Taylor, E.C.; Liu, B.J.Org.Chem.2001,66,3726; Organic ProcessResearch ﹠amp; Development 1999,3184-188.
But these routes exist respectively that the synthetic route step is long, and yield is low, and raw material is difficult to obtain, and severe reaction conditions is not suitable for the shortcoming of large-scale industrial production.
Below this route by people such as Taylor 2003 report, also be the up-to-date synthetic route of visible on the document so far.Though compare with route in the past, yield increases, starting raw material aldehyde instability still needs own synthesizing, thereby step is still long, and total recovery is still lower; Secondly this method is a laboratory process, and will use the big Nitromethane 99Min. of toxicity in the building-up process, therefore also is not suitable for large-scale industrial production.
The contriver has carried out N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-disodium glutamate salt is the exploration of the chemical synthesis process of pemetrexed disodium, a kind of yield height is provided, the reaction conditions gentleness, easy to operation, good product quality, cost are low, be suitable for the method for large-scale industrial production, and in this process, synthesized a kind of new compound intermediate 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester, this intermediate can be in order to synthetic pemetrexed.
(3) summary of the invention
The invention provides a kind of compound, can be used as the intermediate that synthesizes pemetrexed with this compound, described compound is 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester, its chemical formula is suc as formula shown in (IV):
The present invention also provides a kind of preparation above compound 4-[(4-oxo-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester; being raw material suc as formula the 4-shown in (III) (4-oxo butyl) benzoyl-L-glutamate diethyl ester; with brominated reagent under the protection of inert gas in C1～C4 halogenated hydrocarbon solvent in 20 ℃～30 ℃ down reactions, obtain the compound shown in the formula (IV).
Further, in described method, described formula (III) compound is 1: 1～1.5 with the amount of substance ratio of brominated reagent, and the consumption of described halogenated hydrocarbon solvent is 20～30 times of formula (III) compound quality.
Further again, described halogenated hydrocarbon solvent is methylene dichloride or trichloromethane, and described brominated reagent is 5,5-two bromos-2,2-dimethyl-4,6-dicarbapentaborane-1,3-diox or bromo barbituric acid.
Further; prepare described compound 4-[(4-oxo-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester is: after formula (III) compound and methylene dichloride are mixed; add 5 again; 5-two bromos-2; 2-dimethyl-4; 6-dicarbapentaborane-1, the 3-diox, under nitrogen protection in 20 ℃～30 ℃ down reactions.
At preparation described compound 4-[(4-oxo-3-bromine) butyl] in the method for benzoyl-L-glutamate diethyl ester; formula (III) compound makes by following method: the 4-bromobenzene formyl-L-glutamate diethyl ester shown in (II) and 3-butene-1-alcohol under the protection at rare gas element under the effect of the halogenide of palladium acetate catalyst, weakly alkaline reagent, lithium, phase-transfer catalyst in 50～70 ℃ at N; react in the dinethylformamide, make formula (III) compound.Described weakly alkaline reagent is lithium acetate or triethylamine, and the halogenide of described lithium is lithium chloride, lithiumbromide or lithium fluoride.
The described amount of substance ratio that feeds intake is compound (II): weakly alkaline reagent: phase-transfer catalyst: the halogenide of lithium: 3-butene-1-alcohol: acid chloride is 1: 1～3: 1～2: 1～3: 1～1.5: 0.05～0.2, described N, the consumption of dinethylformamide are 5～15 times of compound (II) quality.
Described phase-transfer catalyst is a tetrabutyl ammonium halide, preferred tetrabutylammonium chloride or Tetrabutyl amonium bromide, and the halogenide of described lithium is lithium chloride.
Aforesaid compound 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV) can be in order to preparation N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-glutamate diethyl ester (V), finally in order to make pemetrexed disodium, concrete described 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV) and 2,4-diamino-6-hydroxy pyrimidine is under the effect of condensing agent, in polar solvent, generate the compound shown in the formula V in 35～50 ℃ of reactions, described condensing agent is sodium acetate or potassium acetate, described polar solvent is N, dinethylformamide or acetonitrile water mixed solvent
Further, at described compound 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV) the preparation formula V in, described formula (IV) compound and 2, the amount of substance ratio that feeds intake of 4-diamino-6-hydroxy pyrimidine and condensing agent is 1: 1～1.2: 1.5～2.5, and described polar solvent is that the volume ratio of acetonitrile and water is 1: 1 a mixed solvent.The formula V compound crude product that obtains of reaction can with the tosic acid salify, neutralization obtains purified product then, also can obtain purified product by recrystallization or other purification process.
Described formula V N-[4-[2-(the 2-amino-4 that makes, 7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-glutamate diethyl ester compound, be preparation formula (VII) N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-important intermediate of L-disodium glutamate salt compound
The existing report of prior art, formula (VII) N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-disodium glutamate salt compound claims pemetrexed disodium again, (pemetrexed has another name called LY231514 to pemetrexed, trade(brand)name Alimta) is a kind of novel anti folic acid antimetabolite, action target spot comprises pyrimidine and the purine plurality of enzymes in synthetic, thus have another name called many targets antifol (multi2targeted antifolate, MTA).In external and clinical trial, demonstrate anti-tumor activity widely.Concrete, pemetrexed disodium can make according to laxative remedy, compound (V) reacts in the ethanol of sodium hydroxide and water mixed solvent, acid out then, the compound that obtains is added sodium hydroxide lye adjusting pH value in a certain amount of water be 8.5～9, slowly drip ethanol again, all separate out, filter and promptly get compound (VII) until product.Compound (V) is 1: 4～6 with the amount of substance ratio of sodium hydroxide, and mixed solvent is that water and alcoholic acid volume ratio are water: the mixed solvent of ethanol=1: 0～2, temperature of reaction are 25～30 ℃, and the reaction times is 4～8 hours.
The present invention can make the preparation of pemetrexed disodium be prepared by following route, and reaction formula is expressed as follows:
Contribution of the present invention has been to seek a kind of new for intermediate of producing pemetrexed disodium and preparation method thereof, make that synthetic pemetrexed route is more reasonable, the yield height, the reaction conditions gentleness, easy to operation, good product quality, cost are low, are the methods that is suitable for large-scale industrial production.
(4) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Compound 4-[(4-oxo-3-bromine) butyl] preparation of benzoyl-L-glutamate diethyl ester (IV):
Embodiment 1 4-[(4-oxo-3-bromine) butyl] preparation of benzoyl-L-glutamate diethyl ester (IV)
The amount of substance that feeds intake is than being 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III): 5, and 5-two bromos-2,2-dimethyl-4,6-dicarbapentaborane-1,3-diox=1:1.5;
Mechanical stirring is being housed; add 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III) 37.7g (0.1mol) in three mouthfuls of reaction flasks of the 1500ml of import and export of nitrogen and thermometer; methylene dichloride 1000ml under nitrogen protection, adds 45.0g (0.15mol) 5; 5-two bromos-2; 2-dimethyl-4,6-dicarbapentaborane-1,3-diox; add the back 20-25 ℃ of reaction, TLC follows the tracks of response situation.After reaction finishes, filter, the organic layer each 100mL washed twice of 1N hypo solution, wash with 5% sodium hydrogen carbonate solution 200ml then, with the each 100mL washed twice of saturated aqueous common salt, steaming desolventizes and promptly obtains thick solid 4-[(4-oxo-3-bromine behind the adding anhydrous magnesium sulfate drying at last) butyl] benzoyl-L-glutamate diethyl ester (IV) 48.2g.
Embodiment 2 4-[(4-oxo-3-bromine) butyl] preparation of benzoyl-L-glutamate diethyl ester (IV)
The amount of substance that feeds intake is than being 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III): 5, and 5-two bromos-2,2-dimethyl-4,6-dicarbapentaborane-1,3-diox=1: 1.5, organic solvent change trichloromethane into, consumption 1000ml.
Other material charging capacitys and operating process are with embodiment 1.Obtain thick solid 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV) 48.0g.
Embodiment 3 4-[(4-oxo-3-bromine) butyl] preparation of benzoyl-L-glutamate diethyl ester (IV)
The amount of substance that feeds intake is than being 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III): bromo barbituric acid=1: 1.5;
Mechanical stirring is being housed; add 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III) 37.7g (0.1mol) in three mouthfuls of reaction flasks of the 1500ml of import and export of nitrogen and thermometer; methylene dichloride 1000ml; under protection of inert gas; add 42.9g (0.15mol) bromo barbituric acid; add the back 20-25 ℃ of reaction, TLC follows the tracks of response situation.After reaction finishes, filter, the organic layer each 100mL washed twice of 1N hypo solution, wash with 5% sodium hydrogen carbonate solution 200ml then, at last with the each 100mL washed twice of saturated aqueous common salt, add to steam behind the anhydrous magnesium sulfate drying and desolventize, obtain thick solid 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV) 48.5g.
The preparation method of compound 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III):
The preparation of embodiment 4 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III)
The amount of substance that feeds intake is than being 4-bromobenzene formyl-L-glutamate diethyl ester (II): lithium acetate: Tetrabutyl amonium bromide: lithium chloride: 3-butene-1-alcohol: acid chloride=1: 2: 1.5: 2.5: 1.05: 0.08.
Mechanical stirring is being housed, in three mouthfuls of reaction flasks of the 500ml of import and export of nitrogen and thermometer, is adding 4-bromobenzene formyl-L-glutamate diethyl ester (II) (38.6g, 0.1mol), lithium acetate (13.2g, 0.2mol), Tetrabutyl amonium bromide (48.4g, 0.15mol), lithium chloride (10.6g, 0.25mol), N, dinethylformamide 300ml stirred 10 minutes, add acid chloride 1.8g, 3-butene-1-alcohol (7.6g, 0.105mol), be warming up to 68-70 ℃ of reaction, follow the tracks of response situation with TLC.Reaction finishes suitably to cool off the back by one deck diatomite filtration, and uses N, the each 50mL washing leaching cake of dinethylformamide three times, and filtrate is preserved.In installing three mouthfuls of reaction flasks of churned mechanically 2000ml in advance, add the 1000ml frozen water, slowly above-mentioned filtrate is added then, add the back and under this temperature, stirred one hour, filter, obtain the khaki color solid.Crude product gets off-white color solid 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III) with cyclohexane and ethyl acetate mixed solvent recrystallization, obtain 24g compound (III) after 50 ℃ of following dryings of vacuum (20mmHg), 86～88 ℃ of fusing points, yield 63.7%, its materialization data are as follows:
1HNMR(d6-DMSO)δ：9.65(1H，t，J＝1.5Hz)，7.79(2H，d，J＝7.5Hz)，7.30(2H，d，J＝8.0Hz)，6.32(1H，s)，4.44(1H，q，J＝5.0Hz)，4.11(2H，q，J＝7.0Hz)，4.05(2H，q.J＝7.0Hz)，2.99(2H，tJ＝7.0Hz)，2.87(2H，t，J＝7.0Hz)，2.63(2H，t，J＝7.7Hz)，2.43(2H，td，J＝7.4，1.5Hz)、1.82(2H，n)，1.19(3H，t，J＝6.5Hz)，1.17(3H，t，J＝6.5Hz).
ESI-MS(M/Z)：377，400(M+Na)
The preparation of embodiment 5 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III)
The amount of substance that feeds intake is than being 4-bromobenzene formyl-L-glutamate diethyl ester (II): triethylamine: Tetrabutyl amonium bromide: lithium chloride: 3-butene-1-alcohol: acid chloride=1: 2: 1.5: 2.5: 1.05: 0.08.
The triethylamine charging capacity is 20.2g, and all the other raw material charging capacitys and operating process are with embodiment 4.Get 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III) 19.2g, yield 51%, 86～88.2 ℃ of fusing points, the materialization data are with embodiment 4.
The preparation of embodiment 6 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III)
The amount of substance that feeds intake is than being 4-bromobenzene formyl-L-glutamate diethyl ester (II): lithium acetate: tetrabutylammonium chloride: lithium chloride: 3-butene-1-alcohol: acid chloride=1: 2: 1.5: 2.5: 1.05: 0.08.
The tetrabutylammonium chloride charging capacity is 41.9g, and all the other raw material charging capacitys and operating process are with embodiment 4.Get 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III) 23.8g, yield 63.2%, 86～87.9 ℃ of fusing points, the materialization data are with embodiment 4.
Synthesizing of embodiment 7 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III)
The amount of substance that feeds intake is than being 4-bromobenzene formyl-L-glutamate diethyl ester (II): lithium acetate: tetrabutylammonium chloride: lithiumbromide: 3-butene-1-alcohol: acid chloride=1: 2: 1.5: 2.5: 1.05: 0.08.
The lithiumbromide charging capacity is 21.5g, and the tetrabutylammonium chloride charging capacity is 41.9g, and all the other raw material charging capacitys and operating process are with embodiment 4.Get 4-(4-oxo butyl) benzoyl-L-glutamate diethyl ester (III) 24.5g, yield 65.0%, 86～87.6 ℃ of fusing points, the materialization data are with embodiment 4.Compound 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV) is at preparation N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-application in the L-glutamate diethyl ester (V)
Embodiment 8 N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-glutamate diethyl ester (V) synthetic
The amount of substance that feeds intake is than being 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV): 2,4-diamino-6-hydroxy pyrimidine: sodium acetate=1: 1.1: 1.8.
In three mouthfuls of reaction flasks of the 500ml that mechanical stirring and thermometer are housed, drop into 2,4-diamino-6-hydroxy pyrimidine (14.6g, 0.12mol), sodium acetate (16.1g, 0.19mol), acetonitrile/water (volume ratio 1: 1) 300ml, stir the thick solid phase prod 4-[(4-oxo-3-bromine that slowly adds preparation down) butyl] benzoyl-L-glutamate diethyl ester (IV) 48g, because compound (IV) decomposes easily, to directly carry out this reaction after the preparation, be warming up to 40-42 ℃ of reaction 2-3 hour, follow the tracks of response situation with TLC.After reaction finishes, be cooled to 0-5 ℃ of filtration, the crude product that obtains gets product N-[4-[2-(2-amino-4 through the mixed solvent recrystallization of ethylene dichloride and methyl alcohol, 7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-glutamate diethyl ester (V), dry 38.2g, two step of the bromo of preparation formula (IV) and the condensation of this reaction total recovery 79.0%, HPLC purity (area normalization method) is 99.15%.Fusing point is greater than 250 ℃ (decomposition), materialization data and document Edward C.Taylor
*And Bin Liu
*J.Org.Chem.2003,68, the 9938-9947 report conforms to.
Embodiment 9 N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-glutamate diethyl ester (V) synthetic
The amount of substance that feeds intake is than being 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester (IV): 2,4-diamino-6-hydroxy pyrimidine: potassium acetate=1: 1.1: 1.8.
Operating process is with embodiment 8.Obtain N-[4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] close pyridine-5-yl) ethyl] benzoyl]-L-glutamate diethyl ester (V), dry 37.5g, the bromo of preparation formula (IV) and two step of the condensation of this reaction total recovery 77.6%, HPLC purity (area normalization method) is 99.10%.Fusing point is greater than 250 ℃ (decomposition), materialization data and document EdwardC.Taylor
*And Bin Liu
*J.Org.Chem.2003,68, the 9938-9947 report conforms to.
Claims (10)
1. compound, 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester, it is characterized in that its chemical formula is suc as formula shown in (IV):
2. one kind prepares compound 4-[(4-oxo as claimed in claim 1-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester; it is characterized in that being raw material suc as formula the 4-shown in (III) (4-oxo butyl) benzoyl-L-glutamate diethyl ester; with brominated reagent under the protection of inert gas in C1～C4 halogenated hydrocarbon solvent in 20 ℃～30 ℃ down reactions, obtain the compound shown in the formula (IV)
3. the described compound 4-[(4-oxo of preparation as claimed in claim 2-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester, it is characterized in that described formula (III) compound and the amount of substance ratio of brominated reagent are 1: 1～1.5, the consumption of described halogenated hydrocarbon solvent is 20～30 times of formula (III) compound quality.
4. the described compound 4-[(4-oxo of preparation as claimed in claim 2-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester, it is characterized in that described halogenated hydrocarbon solvent is methylene dichloride or trichloromethane.
5. the described compound 4-[(4-oxo of preparation as claimed in claim 2-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester, it is characterized in that described brominated reagent is 5,5-two bromos-2,2-dimethyl-4,6-dicarbapentaborane-1,3-diox or bromo barbituric acid.
6. the described compound 4-[(4-oxo of preparation as claimed in claim 2-3-bromine) butyl] method of benzoyl-L-glutamate diethyl ester; it is characterized in that described method is: after formula (III) compound and methylene dichloride mixing; add 5 again; 5-two bromos-2; 2-dimethyl-4; 6-dicarbapentaborane-1, the 3-diox reacts down in 20 ℃～30 ℃ under nitrogen protection.
7. a butyl compound as claimed in claim 1 (IV) 4-[(4-oxo-3-bromine)] application of benzoyl-L-glutamate diethyl ester in the compound of preparation shown in formula V
8. compound 4-[(4-oxo as claimed in claim 7-3-bromine) butyl] application of benzoyl-L-glutamate diethyl ester, it is characterized in that described 4-[(4-oxo-3-bromine) butyl] benzoyl-L-glutamate diethyl ester and 2,4-diamino-6-hydroxy pyrimidine is under the condensing agent effect, in polar solvent, generate the formula V compound in 35～50 ℃ of reactions, described condensing agent is sodium acetate or potassium acetate, described polar solvent is N, dinethylformamide or acetonitrile water mixed solvent.
9. compound 4-[(4-oxo as claimed in claim 8-3-bromine) butyl] application of benzoyl-L-glutamate diethyl ester, it is characterized in that described formula (IV) compound and 2, the amount of substance ratio that feeds intake of 4-diamino-6-hydroxy pyrimidine and condensing agent is 1: 1～1.2: 1.5～2.5.
10. compound 4-[(4-oxo as claimed in claim 8-3-bromine) butyl] application of benzoyl-L-glutamate diethyl ester, it is characterized in that described acetonitrile water mixed solvent is that acetonitrile and water volume ratio are 1: 1 mixed solvent.
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| 培美曲塞二钠的合成 朱高军，中国医药工业杂志，第36卷第12期 2005 * |
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