CN103086912A - Method for preparing pemetrexed and pemetrexed intermediate - Google Patents
Method for preparing pemetrexed and pemetrexed intermediate Download PDFInfo
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- CN103086912A CN103086912A CN2012104545658A CN201210454565A CN103086912A CN 103086912 A CN103086912 A CN 103086912A CN 2012104545658 A CN2012104545658 A CN 2012104545658A CN 201210454565 A CN201210454565 A CN 201210454565A CN 103086912 A CN103086912 A CN 103086912A
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Abstract
The invention relates to a method for preparing pemetrexed and a pemetrexed intermediate, namely N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-L-glutamic acid dimethyl ester and a method for preparing a medicine salt of the compound. The invention explores a chemical synthesis method of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt, namely pemetrexed disodium salt, and provides a method for preparing the N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt (IV) from the new compound N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-L-glutamic acid dimethyl ester (I). According to the method, the yield is high, reaction condition is mild, the operation is simple, convenient, and easy, the product quality is good, the cost is low, and the pemetrexed and the pemetrexed intermediate are suitable for large-scale industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to new intermediate N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-Pidolidone dimethyl ester and the application in synthetic pemetrexed thereof.
Background technology
Pemetrexed disodium (pemetrexed disodium), (2-amino-4 for chemistry N-[4-[2-by name, 7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-the Pidolidone disodium salt, pemetrexed (pemetrexed disodium, Alimta) be a kind of " many target spots antifol ", developed as the anti-metabolism anticarcinogen by Lilly Co., Eli.; This antimetabolite has blocked that DNA copies and the needed enzyme of cell fission---glycine ribonucleoside thymidylate synthetase (TS), transformylase (GARFT), Tetrahydrofolate dehydrogenase (DHFR); make cell fission stop at the S phase, thereby suppress the growth of cancer cell.It has restraining effect to kinds cancer, it is the medicine that first treatment malignant pleural mesothelioma obtains promising result, and obtain FDA Food and Drug Administration (FDA) approval on February 5th, 2004, being used for the treatment of to perform the operation maybe should not carry out the malignant pleural mesothelioma of operation.On August 19th, 2004, U.S. FDA ratified second indication of pemetrexed-with late period or the Metastatic Nsclc (NSCI C) of Combined with Cisplatin for The Treatment.The research of relevant pemetrexed treatment NSCIC has made some progress, and this medicine probably becomes the line medication for the treatment of NSCIC.
Pemetrexed has a lot of synthetic routes to report for work:
Route 1 is that route is as follows by patent EP 0589720:
This law is reaction conditions gentleness, easy handling in general; But using expensive hexa methyl silazane and Iodotrimethylsilane, in addition starting raw material 4-(4-carbomethoxyphenyl) butyraldehyde is not easy to obtain, and must be synthetic from other approach.
Route 2 is US Patent No. 6013828, and route is as follows:
Route 2
This law is raw materials used relatively cheap and easy to get, and reaction conditions is gentle, and operation is held relatively
Easily, but operational path is long, and reactions steps is more, complex operation.
Route 3 is European patent EP 0432677, and route is as follows:
This law synthetic route is short, reaction Bu Sudden is few, but starting raw material is not easy to obtain, and intermediate contains acetylene bond, needs high-pressure hydrogenation to reduce, and is not suitable for suitability for industrialized production.
Route 4 is world patent WO2000011004, and route is as follows:
This law starting raw material price is higher and be not easy to obtain, and synthetic route is longer.
Above-mentioned synthetic route exists anhydrous response will remove height, and the long or restricted problem of industrialization of reactions steps need to be more suitable for the pemetrexed preparation method of suitability for industrialized production.
Summary of the invention
The present invention has carried out N-[4-[2-, and (2-amino-4; 7-dihydro-4-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-yl) ethyl] benzoyl]-the both explorations of the chemical synthesis process of pemetrexed disodium salt of Pidolidone disodium salt, the method by the synthetic IV of I is provided.The method yield is high, and reaction conditions is gentle, and is easy to operation, and good product quality, cost are low, suitability for mass industrialized production.
Use new compound N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-(2-amino-4 for the synthetic N-[4-[2-of Pidolidone dimethyl ester (I); 7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-route 5 reaction formula of Pidolidone disodium salt (IV) as
The carbon atom that wherein indicates * is configured as L-type
Intermediate (I) N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-the Pidolidone dimethyl ester is take the 4-as shown in (VIII) (4-oxo butyl) benzoyl-Pidolidone dimethyl ester as raw material; reacting under protection of inert gas, obtain the compound shown in formula I with brominated reagent in C1 C4 halogenated hydrocarbon solvent under 30 ° of C of 20 ° of C.
In described method, the molar ratio of described formula (VIII) compound and brominated reagent is 1:1 1.5, and the consumption of described halogenated hydrocarbon solvent is 20 30 times of formula (VIII) compound quality.
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.
In the method for preparation described compound 4-(4-oxo butyl)-benzoyl-L-glutamic acid dimethyl ester; formula (VIII) compound makes by following method: the 4-bromobenzene formyl as shown in (VII)-Pidolidone dimethyl ester and 3-butene-1-ol 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 ° of C at N; react in dinethylformamide, make formula (VIII) 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 molar ratio that feeds intake is compound (VII): weakly alkaline reagent: phase-transfer catalyst: the halogenide of lithium: 3-butene-1-ol: acid chloride is 1:1 3:1 2:1 3:1 1.5:0.05 0.2,
The consumption of described DMF is 5 15 times of compound (VII) quality.
Described phase-transfer catalyst is tetrabutyl ammonium halide, preferred tetrabutylammonium chloride or Tetrabutyl amonium bromide, and the halogenide of described lithium is lithium chloride.
compound N as above-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-Pidolidone dimethyl ester (I) can carry out N-[4-[2-(2-amino-4 in order to prepare the present invention, 7-dihydro-4-oxo-1H-pyrrolo-[2, 3-d] pyrimidine-5-yl) ethyl] benzoyl]-Pidolidone dimethyl ester (II), finally in order to make pemetrexed disodium (IV), concrete described N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-Pidolidone dimethyl ester (I) and 2, 4-diamino-6-hydroxy pyrimidine is under the effect of condensing agent, generate the compound shown in formula II in 35 50 ° of C reactions in polar solvent, described condensing agent is sodium acetate or potassium acetate, described polar solvent is N, dinethylformamide or acetonitrile water mixed solvent
At described N-[3-bromine 4-(butyraldehyde-4-yl)-benzoyl]-Pidolidone dimethyl ester (I) the preparation formula II in; described formula I compound and 2; the molar 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 the mixed solvent of 1:1.The formula II compound crude product that obtains of reaction can with the tosic acid salify, then neutralization obtains purified product, also can obtain purified product by recrystallization or other purification process.
Pemetrexed disodium can make according to laxative remedy, compound (II) reacts in the ethanol of sodium hydroxide and water mixed solvent, then acid out, adding sodium hydroxide lye to regulate pH value in-quantitative water the compound that obtains is 8.5 9, slowly drip again ethanol, until product is all separated out, filter and namely get compound (IV).Compound (II) is 1:4 6 with the molar ratio of sodium hydroxide, and mixed solvent is that the volume ratio of water and ethanol is water: the mixed solvent of ethanol=1:0 2, temperature of reaction are 25 30 ° of C, and the reaction times is 48 hours.
Embodiment
The preparation of embodiment 1:N-(to benzoyl bromide)-Pidolidone dimethyl ester (VII)
:
Add parabromobenzoic acid (VI) 81g (0. 403mol) in there-necked flask, add the 500ml thionyl chloride, reflux.After insoluble solids disappeared, thionyl chloride was reclaimed in underpressure distillation, obtains the off-white color solid.This solid uses the dissolving of 1000ml methylene dichloride, adds Pidolidone dimethyl ester hydrochloride 91g (0. 43mol), is cooled to 5 ° below C, drips triethylamine 120g (l. 2mol), reacts 2h under room temperature.Add the 500ml methylene dichloride, washing, anhydrous sodium sulfate drying.Distillation is removed
Solvent gets white solid 140. 8g, yield 86.3%.
1HNMR(DMS0-d
6,600MHz) δ8.81 (d, 1H),7.87(d,2H),7.66(d,2H),4.42 (q, 1H),3.69 (s,2H), 3.65 (s,2H), 2.44 (t,2H), 2.07 2.11 (m,1H),1.96 2.02 (m,1H),1.15 1.19(m,6H)。
The preparation of embodiment 2:4-(4-oxo butyl) benzoyl-Pidolidone dimethyl ester (VIII)
:
Mechanical stirring is being housed; in three mouthfuls of reaction flasks of the 500ml of import and export of nitrogen and thermometer; add N-(to benzoyl bromide)-Pidolidone dimethyl ester (VII) (38.3g; O.lmol), lithium acetate (13.2g; 0.2mol) tetrabutyl phosphonium bromide is by (48.4g; 0.15mol); lithium chloride (10.6g, 0.25mol), N; dinethylformamide 300ml; stirred 10 minutes, and added acid chloride 1.8g, 3-butene-1-ol (7.6g, 0.105mol); be warming up to 68-70 ° of C reaction, follow the tracks of response situation with TLC.Reaction finish suitably cooling after by one deck diatomite filtration, and with the each 50mL washing leaching cake of DMF three times, filtrate is preserved.Add the 1000ml frozen water in installing in advance three mouthfuls of reaction flasks of churned mechanically 2000ml, then slowly above-mentioned filtrate is added, stirred one hour at this temperature after adding, filter, obtain the khaki color solid.Crude product gets off-white color solid 4-(4-oxo butyl) benzoyl-Pidolidone dimethyl ester (VIII) with hexanaphthene and ethyl acetate mixed solvent recrystallization, obtain 24g compound (III), yield 63.7% after drying under 50 ° of C of vacuum (20mmHg).
1HNMR(DMS0-d
6,400MHz)δ9.67 (s,1H) ,8.56 (d, 1H) ,7.84(d,2H),7.36 (dd, 2H) 4.45 (dd, 1H),3.69 (s, 2H),3.66 (s, 2H),
2.65 (t,2H),2.50 (t,2H),2.46 (t,2H) ,2.10 2.15(m,1H), 1.99 2.11 (m,1H), 1 82 1.89 (m,2H),1.15 1.21(m,6H)。
Embodiment 3:N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-preparation of Pidolidone dimethyl ester (I):
Mechanical stirring is being housed; add 4-(4-oxo butyl) benzoyl-Pidolidone dimethyl ester (VIII) 37.4g (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; after adding, 20-25 ° of C reaction, TLC follows the tracks of response situation.After anti-Ying Jie Bouquet; filter; organic layer is with the 1 each 100mL washed twice of N hypo solution; then with 5% sodium hydrogen carbonate solution 200ml washing; at last with the each lOOmL washed twice of saturated aqueous common salt, add to steam to desolventize after anhydrous magnesium sulfate drying namely to obtain thick solid N-[3-bromo-4-(butyraldehyde-4-yl)-benzoyl]-Pidolidone dimethyl ester (I) 48.2g.
1HNMR(DMS0-d
6,400MHz)δ9.49 (s,1H),8.65 (t,1H),7.82 (d,2H),7.34 (dd,2H), 4.83 (q,0.5H),4.63 (q,0.5H) ,4.40 4.46 (q,1H),3.69 (s,2H),3.64 (s,2H) ,2.73 2.89(m,2H),2.43 (t,2H),1.99 2.11 (m,2H),1.88 1.98 (m,2H),1.10 1.23(m,6H)。
Embodiment 4:N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-preparation of Pidolidone dimethyl ester (II):
Drop into 2 in three mouthfuls of reaction flasks of the 500ml that mechanical stirring and thermometer are housed; 4-diamino-6-hydroxy pyrimidine (14.6g; 0.12mol); sodium acetate 16.1g; 0.19mol); acetonitrile/water (volume ratio 1:1) 300ml; whisk down the thick solid phase prod N-[3-bromo-4-(butyraldehyde that slowly adds preparation-4-yl)-benzoyl]-Pidolidone dimethyl ester (I) 48g; because compound (I) easily decomposes; to directly carry out this reaction after preparation; be warming up to 40-42 ° of C reaction 2-3 hour, follow the tracks of response situation with TLC.After reaction finishes; being cooled to 0-5 ° of C filters; 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-oxo-1H-pyrrolo-[2; 3-d] pyrimidine-5-yl) ethyl] benzoyl]-Pidolidone dimethyl ester (II); dry to get 38.2g, the bromo of preparation formula II and two step of the condensation of this reaction total recovery 79.0%
1HNMR (DMS0-d
6, 600MHz)δ10.54 (s,1H),10.09 (s,1H),8. 55 (d, 1H) ,7.78(d,2H),7.28 (d,2H),6.30 (s,1H) ,5. 94(s,2H),4.45 (q,1H),3.69(s,2H),3.64(s,2H),2. 99(t,2H),2. 87 (t, 2H),2.24 (t,2H),2.08 2.12 (m,1H),1.98 2.05 (m,1H),1.12 1.20 (m,6H).
Proof by experiment: the method yield is high, and reaction conditions is gentle, and is easy to operation, and good product quality, cost are low, suitability for mass industrialized production.
If the content that is not described in detail is arranged in this specification sheets, should be the known technology of those skilled in the art, repeat no more herein.
Claims (2)
One kind prepare that the compound that represents with the following formula IV or its can do will be with the method for salt
The carbon atom that wherein indicates * is configured as L-type,
The method is characterized in that: be comprised of following steps:
(a), chemical compounds I and 2,4-diamino-6-hydroxy pyrimidine reaction obtains compound ii
(b), compound ii obtains the compound III through hydrolysis reaction
(c), the compound III obtains compounds Ⅳ through salify
The carbon atom that wherein indicates * is configured as L-type.
3, tell according to claim 2 the preparation pemetrexed method, it is characterized by in step (a), reaction solvent is water, acetonitrile, glacial acetic acid, ethyl acetate, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, N, dinethylformamide or mixed solvent wherein, temperature of reaction is 30~60 ℃, and the reaction times is 2 hours to 6 hours.
4, tell according to claim 2 the preparation pemetrexed method, it is characterized by in step (a), condensing agent used is sodium acetate or potassium acetate.
5, tell according to claim 2 the preparation pemetrexed method, it is characterized by in step (a), the molar ratio that feeds intake of compound ii and 2,4-diamino-6-hydroxy pyrimidine and condensing agent is 1:1~1.2:1.5~2.5.
6, according to claim 3, reaction solvent is selected from the mixed solvent of acetonitrile and water, and ratio is 1:1.
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CN105111214A (en) * | 2015-08-31 | 2015-12-02 | 江西农业大学 | Preparation method of pemetrexed disodium |
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