CN110305136A - A kind of pemetrexed disodium intermediate and preparation method thereof - Google Patents

A kind of pemetrexed disodium intermediate and preparation method thereof Download PDF

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CN110305136A
CN110305136A CN201810227832.5A CN201810227832A CN110305136A CN 110305136 A CN110305136 A CN 110305136A CN 201810227832 A CN201810227832 A CN 201810227832A CN 110305136 A CN110305136 A CN 110305136A
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added
stirring
ethyl
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臧超
夏明军
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Lunan Pharmaceutical Group Corp
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention belongs to pharmaceutical technology fields, and in particular to a kind of pemetrexed disodium intermediate III and preparation method thereof.Step includes: that DMF, triethylamine stirring and dissolving is added in 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid, reacts with R-CL, intermediate II is obtained after processing；Using intermediate I and intermediate II as raw material, in N, the effect of N- carbonyl dimidazoles is lower to occur condensation reaction, then reacts with p-methyl benzenesulfonic acid, obtains intermediate III.The reaction that the present invention be protected from itself to amino generates impurity VI, while preventing the unstable oxidation stain conditions of problems occurred during the reaction of amino mild, and high income, product is relatively stable, is conducive to actual production.

Description

A kind of pemetrexed disodium intermediate and preparation method thereof
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pemetrexed disodium intermediate and preparation method.
Background technique
Pemetrexed is in a kind of structure be containing core pyrrolopyrimidine group folic acid resisting preparation, it is intracellular by destroying The normal metabolic processes of folate-dependant inhibit cellular replication, to inhibit the growth of tumour.In vitro study is shown, it is bent to train U.S. Plug is able to suppress the activity of thymidylate synthetase, dihyrofolate reductase and glycinamide ribonucleotide formyl transferase, these enzymes All it is enzyme necessary to synthesis folic acid, participates in the biological synthesis process again of thymidylic acid and purine nucleotides.Training U.S. is bent Plug disodium is multiple target point antifol, interferes necessary folate-dependant metabolic process performance antiproliferative in proliferation process living Property, it is active to a variety of solid tumors.It has been approved in Europe for treating malignant pleural mesothelioma and non-small cell lung cancer at present, It is approved in the U.S. for treating malignant pleural mesothelioma within 2004.
Patent and administrative protection retrieval show that pemetrexed does not have compound patent in China, and offshore company is in China Shen Please preparation patent and composition patent, but not yet authorize.Specific medicament and treatment as treatment malignant pleural mesothelioma The potential drugs of advanced lung cancer, have obtained pursuing for numerous pharmacy corporations since listing, have more domestic pharmacy enterprises at present Industry obtains production official written reply, and market prospects are very good.
Disclosed pemetrexed synthetic route mainly includes three:
1. cyclic that pyrimidone, hydrochloric acid act on through condensation and guanidine with ethyl chloroacetate and bromo- 1, the 1- diethoxyethane of 2- Lower closed loop obtains Pyrrolopyrimidine thion, acylation, two iodos, the de- iodine of selectivity and N- (4- acetylenylbenzene formoxyl)-Pidolidone two Methyl esters condensation, catalytic hydrogen reduction obtain pemetrexed, and this method route is longer, and intermediate needs to purify, and is unfavorable for practical life It produces.
2. with 4- (2- formylethyl) ethyl benzoate and paraformaldehyde under the effect of N- ethyl-benzothiazole bromide Reaction is condensed with ethyl cyanoacetate, then is reacted with guanidine and obtained 4- [2- (2- amino -4,7- dihydro -4- under the effect of closed loop sodium hydroxide Oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] Pei Mei is obtained after benzoic acid, with the ester condensation of Pidolidone diethyl, hydrolysis Qu Sai, this method raw material are not easy to obtain, and are unfavorable for actual production.
3. with 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid For starting material, pemetrexed disodium is obtained after condensation, at salt, hydrolysis with Pidolidone diethyl ester hydrochloride, this route is former Material is easy to get, and reaction step is shorter, easy to operate, advantage of lower cost, is suitble to industrialized production.But this process route exist compared with It is mostly insufficient, it is mainly manifested in N- { 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) second Base] benzoyl-Pidolidone diethylester toluene fulfonate (structure V) preparation used in starting material Pemedolac, reaction live Property site is more, causes by-product more, it is more difficult to control, the content of especially impurity VI (structure such as formula VI) is up to 5-10%. To reach quality requirement, it is necessary to which, by 2-3 purification this intermediate V, lower so as to cause whole yield, higher cost accounts for whole The large percentage of a pemetrexed disodium cost of material.
Summary of the invention
In order to overcome in the prior art pemetrexed disodium prepare lower yield, high production cost, unstable degradable pure Low problem is spent, the present invention provides a kind of pemetrexed disodium intermediate III and preparation method thereof and pemetrexed disodiums IV Preparation method.
First aspect present invention provides a kind of pemetrexed disodium intermediate III, and structure is as follows:
Wherein, R is selected from one of benzyl, trityl, p-toluenesulfonyl.
Another aspect of the present invention provides the preparation method of pemetrexed disodium intermediate III, comprising the following steps:
4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid is added Enter DMF, triethylamine stirring and dissolving, reacted with R-CL, intermediate II is obtained after processing；
Using intermediate I Pidolidone diethylester and intermediate II as raw material, in N, the effect of N- carbonyl dimidazoles is lower to contract Reaction is closed, is then reacted with p-methyl benzenesulfonic acid, obtains intermediate III；
Specifically, III preparation method of intermediate the following steps are included:
4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid is added Enter DMF, triethylamine, be warming up to 30 DEG C of stirring and dissolvings, R-CL is added dropwise, insulation reaction 1 hour, evaporated under reduced pressure DMF, pure water is added and stirs It mixes, adjusts pH to 5-6 with dilute hydrochloric acid, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain intermediate II；
DMF stirring and dissolving is added in intermediate II, N is added, N- carbonyl dimidazoles, 50-60 DEG C is reacted 2 hours, in addition Mesosome I is warming up to 70-80 DEG C and reacts 3 hours, evaporated under reduced pressure, after methylene chloride dissolution is added, pours into the mixed of pure water and triethylamine It closes in solution and stirs liquid separation, separate organic phase, wash, drying is evaporated, and absolute ethyl alcohol and stirring dissolution is added, p-methyl benzenesulfonic acid is added Reaction 1 hour, cool down crystallization, filters, dries to obtain intermediate III.
Preferably, 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first The molar ratio of acid and R-CL are 1:1-2, more preferable 1:1.5.
Preferably, the molar ratio of the preparation method of pemetrexed disodium, intermediate II and intermediate I is 1:1-1.8.
Preferably, the molar ratio of the preparation method of pemetrexed disodium, intermediate II and p-methyl benzenesulfonic acid is 1:1-1.8.
Preferably, intermediate II and N, the molar ratio of N- carbonyl dimidazoles are 1:1.2-1.8.
Pemetrexed disodium intermediate I of the present invention, chemical name are as follows: Pidolidone diethylester, structure are as follows:
The preparation method of intermediate I, comprising the following steps:
Using Pidolidone diethyl ester hydrochloride as starting material, potassium carbonate is deacidification agent, is carried out by solvent of methylene chloride Depickling reaction, obtains light yellow oil intermediate I Pidolidone diethylester.
A kind of intermediate III is preparing the purposes in pemetrexed disodium.
Third aspect present invention additionally provides a kind of method that intermediate III is used to prepare pemetrexed disodium, including following Step:
Intermediate III sloughs p-methyl benzenesulfonic acid, ester hydrolysis, amide hydrolysis in sodium hydroxide solution, then obtains at sodium salt Pemetrexed disodium IV；
Synthetic route is as follows:
Specifically, the preparation method of pemetrexed disodium, comprising the following steps:
Intermediate III is mixed with sodium hydroxide solution, complete molten rear 10% hydrochloric acid solution that is added dropwise adjusts PH to 2-3, stirring analysis Crystalline substance filters, and filter cake is added dehydrated alcohol and is warming up to 50-60 DEG C of stirring and dissolving, adjusts PH to 6-7 with 20% sodium hydroxide solution and stirs Crystallization, heat filter are mixed, filtrate is refunded in bottle, and 50% sodium hydroxide solution crystallization is added, filters, and vacuum drying obtains pemetrexed two Sodium.
Superiority of the invention is shown:
(1) intermediate III is prepared using intermediate I and intermediate II as raw material, due to-the NH of intermediate II2It is protected, It avoids intermediate II autoreactivity and generates VI compound of impurity, the quality and yield of intermediate III greatly improved, be produced into Originally it declines to a great extent.
(2) preparing pemetrexed disodium with intermediate III for raw material can complete to take off in ethanolic sodium hydroxide solution Acid, hydrolysis, salt-forming reaction, easy to operate, mild condition do not need to carry out special remove-insurance reaction, but since amino receives Protection, it is therefore prevented that the oxidative degradation of amino, the quality and purity of final products greatly improve, and purity is greater than 99.85%.
Specific embodiment
Embodiment 1:
The preparation of Pidolidone diethylester:
It accurately weighs Pidolidone diethyl ester hydrochloride (48g 0.2mol) to be added in 500ml four-hole bottle, it is pure that 120ml is added It after water stirring and dissolving, is added 18g carbonic acid nak response 0.5 hour, 100ml methylene chloride is added and stirs liquid separation, water layer uses pure water again 80ml × 3 is extracted three times, is collected organic phase, is evaporated to obtain product Pidolidone diethylester (molar yield 98.1%, purity after dry 93.9%).
Embodiment 2
4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Preparation
Weigh 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (60g 0.2mol) is added in 500ml four-hole bottle, 200mlDMF is added, triethylamine 60.6g is warming up to 30 DEG C of stirring and dissolvings, drop Add benzyl chloride (0.2mol), be warming up to 50 DEG C of insulation reactions 1 hour, evaporated under reduced pressure DMF, the stirring of 200ml pure water is added, with dilute salt For acid for adjusting pH to 5, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen - 3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 95.8%, purity 99.0%).
4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Mass spectrum
[M-H]+=387.15.
1H-NMR:1H NMR(400MHz,D2O) δ=12.12 (s, 1H)；8.15 (d, 2H, J=8.20Hz)；7.58(d, 2H, J=8.20Hz)；7.31 (d, 2H, J=8.21Hz)；7.29 (d, 1H, J=8.21Hz)；7.27 (d, 1H, J=8.23Hz)； 7.27 (d, 1H, J=8.23Hz)；7.03 (d, 2H, J=8.26Hz)；6.06(s,1H)；4.64 (m, 2H) 2.76~2.92 (m, 2H)；2.70~2.87 (m, 2H)；1.96(s,1H).
13C-NMR:13C NMR (400MHz, D2O) δ: 169.34,160.08,148.74,148.53,146.68, 137.91,130.43,130.43,128.91,128.54,128.54,128.18,128.18,127.91,126.94,126.94, 126.70,117.14,104.97,44.95,37.12,29.43.
Embodiment 3
4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Preparation
Weigh 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (60g 0.2mol) is added in 500ml four-hole bottle, 200mlDMF is added, triethylamine 60.6g is warming up to 30 DEG C of stirring and dissolvings, drop Add benzyl chloride (0.4mol), be warming up to 60 DEG C of insulation reactions 1 hour, evaporated under reduced pressure DMF, the stirring of 200ml pure water is added, with dilute salt For acid for adjusting pH to 6, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen - 3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 96.3%, purity 99.2%).
4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Mass spectrum,1H-NMR、13C-NMR is shown in embodiment 2.
Embodiment 4
4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Preparation
Weigh 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (60g 0.2mol) is added in 500ml four-hole bottle, 200mlDMF is added, triethylamine 60.6g is warming up to 30 DEG C of stirring and dissolvings, drop Add benzyl chloride (0.3mol), be warming up to 60 DEG C of insulation reactions 1 hour, evaporated under reduced pressure DMF, the stirring of 200ml pure water is added, with dilute salt For acid for adjusting pH to 6, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen - 3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 96.9%, purity 99.4%).
4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Mass spectrum,1H-NMR、13C-NMR is shown in embodiment 2.
Embodiment 5
4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first The preparation of acid:
Weigh 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (60g 0.2mol) is added in 500ml four-hole bottle, 200mlDMF is added, triethylamine 40.4g is warming up to 30 DEG C of stirring and dissolvings, drop Add trityl chloride (0.3mol), 35 DEG C insulation reaction 1 hour, evaporated under reduced pressure DMF, be added 200ml pure water stirring, with dilute salt Acid for adjusting pH to 5-6, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- triphen methylamino -4,7- dihydro - 4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 96.3%, purity 99.2%).
4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first The mass spectrum [M-H] of acid+=539.22.
1H-NMR:1H NMR(400MHz,D2O) δ=12.12 (s, 1H)；8.15 (d, 2H, J=8.20Hz)；7.58(d, 2H, J=8.20Hz)；7.33 (d, 6H, J=8.22Hz)；7.30 (d, 2H, J=8.31Hz)；7.29 (d, 1H, J=8.31Hz)； 7.28 (d, 6H, J=8.30Hz)；7.03 (d, 2H, J=8.26Hz)；6.06(s,1H)；2.76~2.97 (m, 2H)；2.70~ 2.92(m,2H)；2.54(s,1H).
13C-NMR:13C NMR (400MHz, D2O) δ: 169.34,160.08,148.74,148.53,146.68, 145.06,145.06,130.43,130.43,129.23,129.23,129.23,129.23,129.23,129.23,128.91, 128.18,128.18,127.91,127.08,127.08,127.08,127.08,127.08,127.08,126.28,126.28, 126.28,126.28,117.14,104.97,78.45,37.12,29.43.
Embodiment 6
4- [2- (2- tolysulfonyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] The preparation of benzoic acid:
Weigh 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (60g 0.2mol) is added in 500ml four-hole bottle, 200mlDMF is added, triethylamine 40.4g is warming up to 30 DEG C of stirring and dissolvings, drop Add paratoluensulfonyl chloride (0.3mol), be cooled to 0-5 DEG C of insulation reaction 1 hour, evaporated under reduced pressure DMF is added 300ml pure water and stirs It mixes, adjusts pH to 5-6 with dilute hydrochloric acid, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- tolysulfonyl Amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 96.7%, purity 98.7%).4- [2- (2- tolysulfonyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] The mass spectrum of benzoic acid
[M-H]+=451.12.
1H-NMR:1H NMR(400MHz,D2O) δ=12.12 (s, 1H)；8.15 (d, 2H, J=8.20Hz)；7.82(d, 2H, J=8.30Hz)；7.58 (d, 2H, J=8.20Hz)；7.31 (d, 2H, J=8.31Hz)；7.03 (d, 2H, J=8.26Hz)； 6.06(s,1H)；2.76~2.97 (m, 2H)；2.70~2.92 (m, 2H)；2.44(s,3H)；2.16(s,1H).
13C-NMR:13C NMR (400MHz, D2O) δ: 169.34,160.08,148.74,148.53,146.68, 140.96,137.61,130.43,130.43,129.34,129.34,128.91,128.35,128.35,128.18,128.18, 127.91,117.14,104.97,37.12,29.43,21.35.
Embodiment 7
N- { 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (64.6g0.19mol) is added in 1L four-hole bottle, and 650mlDMF stirring and dissolving is added, and is warming up to 50 DEG C, and 0.228molN, N- is added Carbonyl dimidazoles, 50-60 DEG C insulation reaction 2 hours, be added intermediate Pidolidone diethylester (0.19mol), be warming up to 70-80 DEG C reaction 3 hours, evaporated under reduced pressure after the dissolution of 800ml methylene chloride is added, poured into the mixed of 1600ml pure water and 160ml triethylamine It closes in solution and stirs liquid separation, separate organic phase, pure water 1600ml × 2 wash twice, and drying is evaporated, and 500ml dehydrated alcohol is added The ethanol solution of 36.1g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state, finishes, back flow reaction for stirring and dissolving 1 hour, cool down crystallization, filter, dry product (molar yield 88.5%, purity 98.9%, VI content of impurity be 0).
N- { 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate mass spectrum [M-H]-=572.26.
1H-NMR:1H NMR(400MHz,(CD3)2SO) δ=7.80 (d, 2H, J=8.26Hz)；7.55~7.66 (m, 2H)；7.35 (d, 2H, J=8.30Hz)；7.30 (d, 2H, J=8.28Hz)；7.29 (d, 1H, J=8.28Hz)；7.28(d,2H, J=8.30Hz)；7.19 (d, 1H, J=8.30Hz)；7.16 (d, 2H, J=7.87Hz)；6.52 (d, 1H, J=2.06Hz)； 4.51(s,1H)；4.43(m,2H)；4.09~4.10 (m, 2H)；4.01(m,2H)；2.93(m,2H)；2.95(m,2H)；2.44 (t, 2H, J=7.49Hz)；2.51(s,1H)；1.29(s,3H)；1.20(s,3H).
13C-NMR(400MHz,(CD3)2SO):δ:172.32,170.32,167.08,157.74,151.06,144.98, 139.11,138.89,131.70,128.80,128.80,128.68,128.68,127.95,127.95,126.90,126.90, 126.76,125.98,125.98,119.53,115.80,99.48,61.02,60.41,44.98,36.18,27.65,23.21, 21.26,14.54。
Embodiment 8
N- { 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (64.6g0.19mol) is added in 1L four-hole bottle, and 650mlDMF stirring and dissolving is added, and is warming up to 50 DEG C, and 0.342molN, N- is added Carbonyl dimidazoles, 50-60 DEG C insulation reaction 2 hours, be added intermediate Pidolidone diethylester (0.342mol), be warming up to 70- 80 DEG C are reacted 3 hours, evaporated under reduced pressure, after the dissolution of 800ml methylene chloride is added, pour into 1600ml pure water and 160ml triethylamine Liquid separation is stirred in mixed solution, separates organic phase, and pure water 1600ml × 2 wash twice, and drying is evaporated, and the anhydrous second of 500ml is added The ethanol solution of 65g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state, finishes, back flow reaction for alcohol stirring and dissolving 1 hour, cool down crystallization, filter, dry product (molar yield 89.3%, purity 99.3%, VI content of impurity be 0).
N- { 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate mass spectrum,1H-NMR、13C-NMR is shown in embodiment 8.
Embodiment 9
N- { 4- [2- (2- tolysulfonyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) second Base] benzoyl-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- tolysulfonyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) second Base] benzoic acid (64.6g 0.19mol) is added in 1L four-hole bottle, 650mlDMF stirring and dissolving is added, is warming up to 50 DEG C, be added 0.342molN, N- carbonyl dimidazoles, 50-60 DEG C insulation reaction 2 hours, be added intermediate Pidolidone diethylester (0.342mol) is warming up to 70-80 DEG C and reacts 3 hours, and evaporated under reduced pressure pours into 1600ml after the dissolution of 800ml methylene chloride is added Liquid separation is stirred in the mixed solution of pure water and 160ml triethylamine, separates organic phase, pure water 1600ml × 2 wash twice, dry to steam It is dry, the dissolution of 500ml absolute ethyl alcohol and stirring is added, the dehydrated alcohol of 65g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state Solution finishes, back flow reaction 1 hour, cool down crystallization, filter, dry product (molar yield 88.7%, purity 99.1% are miscellaneous 0) VI content of matter is.
N- { 4- [2- (2- tolysulfonyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) second Base] benzoyl-Pidolidone diethylester toluene fulfonate mass spectrum [M-H]-=636.22.
1H-NMR:1H NMR(400MHz,(CD3)2SO) δ=7.80 (d, 2H, J=8.26Hz)；7.55~7.66 (m, 2H)；7.35 (d, 2H, J=8.30Hz)；7.30 (d, 2H, J=8.28Hz)；7.29 (d, 1H, J=8.28Hz)；7.28(d,2H, J=8.30Hz)；7.16 (d, 2H, J=7.87Hz)；6.52 (d, 1H, J=2.06Hz)；4.51(s,1H)；4.09~4.10 (m, 2H)；4.01(m,2H)；2.93(m,2H)；2.95(m,2H)；2.44 (t, 2H, J=7.49Hz)；2.51(s,1H)；2.43(s, 3H)；1.29(s,3H)；1.20(s,3H).
13C-NMR(400MHz,(CD3)2SO):δ:172.32,170.32,167.08,157.74,151.06,144.98, 139.11,138.89,131.70,128.80,128.80,128.68,128.68,127.95,127.95,126.90,126.90, 126.76,125.98,125.98,119.53,115.80,99.48,61.02,60.41,44.98,36.18,27.65,24.21, 14.56,14.54。
Embodiment 10
N- { 4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene Formoxyl }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene Formic acid (64.6g0.19mol) is added in 1L four-hole bottle, and 650mlDMF stirring and dissolving is added, and is warming up to 50 DEG C, is added 0.342molN, N- carbonyl dimidazoles, 50-60 DEG C insulation reaction 2 hours, be added intermediate Pidolidone diethylester (0.342mol) is warming up to 70-80 DEG C and reacts 3 hours, and evaporated under reduced pressure pours into 1600ml after the dissolution of 800ml methylene chloride is added Liquid separation is stirred in the mixed solution of pure water and 160ml triethylamine, separates organic phase, pure water 1600ml × 2 wash twice, dry to steam It is dry, the dissolution of 500ml absolute ethyl alcohol and stirring is added, the dehydrated alcohol of 65g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state Solution finishes, back flow reaction 1 hour, cool down crystallization, filter, dry product (molar yield 88.5%, purity 99.0% are miscellaneous 0) VI content of matter is.
N- { 4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene Formoxyl }-Pidolidone diethylester toluene fulfonate mass spectrum [M-H]-=724.32.
1H-NMR:1H NMR(400MHz,(CD3)2SO) δ=7.80 (d, 2H, J=8.26Hz)；7.55~7.66 (m, 2H)；7.35 (d, 6H, J=8.30Hz)；7.30 (d, 2H, J=8.28Hz)；7.29 (d, 1H, J=8.28Hz)；7.28(d,6H, J=8.30Hz)；7.20 (d, 2H, J=8.30Hz)；7.19 (d, 1H, J=8.30Hz)；7.16 (d, 2H, J=7.87Hz)； 6.52 (d, 1H, J=2.06Hz)；4.43(m,1H)；4.09~4.10 (m, 2H)；2.93(m,2H)；2.95(m,2H)；2.44 (t, 2H, J=7.49Hz)；2.29(s,3H)；1.20(m,3H)；1.17(m,3H).
13C-NMR(400MHz,(CD3)2SO):δ:172.32,170.32,167.08,157.74,151.06,146.20, 145.04,145.04,144.98,139.11,138.89,131.70,129.23,129.23,129.23,129.23,129.23, 129.23,128.68,128.68,127.95,127.95,127.05,127.05,127.05,127.05,127.05,127.05, 125.98,125.98,126.23,126.23,126.23,126.23,119.53,115.80,99.48,60.41,52.45, 36.18,26.17,21.26,14.54。
Embodiment 11
The preparation of pemetrexed disodium:
It weighs in 36g sodium hydroxide addition 600ml pure water and is cooled to 30 DEG C hereinafter, N- { 4- [2- is added after stirring and dissolving (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl }-Pidolidone diethyl Ester toluene fulfonate (112.7g 0.16mol) stirring and dissolving, complete molten rear 10% hydrochloric acid solution that is added dropwise adjust PH to 2-3, stirring analysis Crystalline substance filters, and filter cake is added in 1L four-hole bottle, and 500ml dehydrated alcohol is added and is warming up to 50-60 DEG C of stirring and dissolving, with 20% hydrogen-oxygen Change sodium solution and adjust pH to 6-7 stirring and crystallizing, heat is filtered, and filtrate is refunded in bottle, and 50% sodium hydroxide solution 24g is added, and stirring rises Temperature is stirred to react 1 hour to 50 DEG C, is cooled to 0 DEG C, stirring and crystallizing 5 hours, is filtered, vacuum drying, and it is bent to obtain white solid training U.S. It fills in disodium (molar yield 83.5%, purity 99.9%).
The mass spectrum of pemetrexed disodium: [M-2Na-2.5H2O+H]-426.4。
Pemetrexed disodium1H-NMR:1H NMR(400MHz,D2O) δ=7.58 (d, 1H, J=8.20Hz)；7.58(d, 1H, J=8.20Hz)；7.02 (d, 1H, J=8.26Hz)；7.02 (d, 1H, J=8.26Hz)；6.16(s,1H)；4.32(dd, 1H, J=4.78Hz)；2.59(m,2H)；2.59(m,2H)；2.34(m,2H)；2.18(m,1H)；2.06(m,1H).
Pemetrexed disodium13C-NMR:13C NMR (400MHz, D2O) δ: 182.33,179.10,169.84, 160.88,151.74,150.53,146.58,130.43,128.18,128.18,126.91,126.91,118.14,114.97, 98.72,56.00,35.12,34.32,28.43,26.71.
Comparative example 1
4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first The preparation of acid:
Weigh 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (60g 0.2mol) is added in 500ml four-hole bottle, 200mlDMF is added, triethylamine 40.4g is warming up to 30 DEG C of stirring and dissolvings, drop Add trityl chloride (0.5mol), 35 DEG C insulation reaction 1 hour, evaporated under reduced pressure DMF, be added 200ml pure water stirring, with dilute salt Acid for adjusting pH to 5-6, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- triphen methylamino -4,7- dihydro - 4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 92.8%, purity 95.6%).
4- [2- (2- triphen methylamino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first The mass spectrum of acid,1H-NMR、13C-NMR is shown in embodiment 5.
Comparative example 2
N- { 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (64.6g0.19mol) is added in 1L four-hole bottle, and 650mlDMF stirring and dissolving is added, and is warming up to 50 DEG C, and 0.228molN, N- is added Carbonyl dimidazoles, 50 DEG C insulation reaction 2 hours, be added intermediate Pidolidone diethylester (0.475mol), be warming up to 70-80 DEG C Reaction 3 hours, evaporated under reduced pressure pour into the mixing of 1600ml pure water and 160ml triethylamine after the dissolution of 800ml methylene chloride is added Liquid separation is stirred in solution, separates organic phase, and pure water 1600ml × 2 wash twice, and drying is evaporated, and 500ml dehydrated alcohol is added and stirs Dissolution is mixed, the ethanol solution of 90g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state, finishes, back flow reaction 1 is small When, cool down crystallization, filters, dries to obtain product (molar yield 83.1%, purity 92.8%).
N- { 4- [2- (2- benzyl amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate mass spectrum,1H-NMR、13C-NMR is shown in embodiment 7.
Comparative example 3
N- { 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl Base }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (64.6g 0.19mol) is added in 1L four-hole bottle, and 650mlDMF stirring and dissolving is added, and is warming up to 50 DEG C, and 0.38molN, N- is added Carbonyl dimidazoles, 60 DEG C insulation reaction 2 hours, be added Pidolidone diethylester (0.38mol), be warming up to 80 DEG C react 3 hours, Evaporated under reduced pressure is poured into the mixed solution of 1600ml pure water and 160ml triethylamine and is stirred after the dissolution of 800ml methylene chloride is added Liquid separation separates organic phase, and pure water 1600ml × 2 wash twice, and drying is evaporated, and the dissolution of 500ml absolute ethyl alcohol and stirring, reflux is added The ethanol solution of 72g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under state, finishes, back flow reaction 1 hour, cool down crystallization, Filter, dry crude product 87.2g (molar yield 70.1%, purity 92.3%, V content of impurity be 6.52%).
It is added to above-mentioned crude product 87.2g in three mouthfuls of reaction flasks, is added and uses n,N-Dimethylformamide 350ml, be heated to 40-45 DEG C of stirring and dissolving, complete molten rear dropwise addition dehydrated alcohol 700ml, is slowly precipitated solid, is down to room temperature, stirring and crystallizing 1-2h, mistake Filter to obtain solid 69.8g, yield 80.0%.It repeats above-mentioned purification operations 1 time, obtaining solid 55.4g, (purity 98.2%, impurity V contain 0.07%) amount is.
Comparative example 3
55.4gN- { 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine-is added in four-hole bottle 5- yl) ethyl] benzoyl }-Pidolidone diethylester toluene fulfonate and 200ml2mol/l sodium hydroxide solution, stirring 1 is small When, pH=3 is adjusted with the hydrochloric acid solution of 0.5mol/L, gained suspension is heated to 65 DEG C, and temperature control reacts 2.5 hours.It is down to room Temperature, filtering, solid are washed with deionized water, and obtaining N-, ([(2- amino -4,7- dihydro -4- oxo -3H- pyrrolo- [2,3-d] is phonetic by 2- by 4- Pyridine -5- base) ethyl] benzoyl)-Pidolidone.Step gained N- (4- [2- (2- amino -4,7- dihydro -4- on being added in four-hole bottle Oxo -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl)-Pidolidone and 200ml0.5mol/L sodium hydroxide, Stirring 1 hour crosses and filters out insoluble matter, obtains clear solution, is 8 with 0.5mol/L salt acid for adjusting pH, and acquired solution is heated to 50 DEG C, Room temperature is down in stirring 30 minutes, and the mixed solvent (volume ratio 10:1.8) of 300ml ethyl alcohol and dimethyl sulfoxide, stirring is added It 10 minutes, stirs 2 hours, filters at 0 DEG C, the mixed solvent of solid 60ml ethyl alcohol and dimethyl sulfoxide (volume ratio 10: 1.8) it washs, 50 DEG C obtain pemetrexed disodium, yield 61.3%, purity 96.9% in vacuum drying 5 hours.
Mass spectrum, 1H-NMR, 13C-NMR of pemetrexed disodium are shown in embodiment 11.

Claims (9)

1. a kind of pemetrexed disodium intermediate III, structure is as follows:
Wherein, R is selected from one of benzyl, trityl, p-toluenesulfonyl.
2. a kind of preparation method of pemetrexed disodium intermediate III, which comprises the following steps:
4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid is added DMF, triethylamine stirring and dissolving, react with R-CL, and intermediate II is obtained after processing；
Using intermediate I Pidolidone diethylester and intermediate II as raw material, in N, the effect of N- carbonyl dimidazoles is lower to occur condensation instead It answers, is then reacted with p-methyl benzenesulfonic acid, obtain intermediate III.
3. the preparation method of intermediate III according to claim 2, which comprises the following steps:
4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid is added DMF, triethylamine are warming up to 30 DEG C of stirring and dissolvings, and R-CL is added dropwise, insulation reaction 1 hour, evaporated under reduced pressure DMF, pure water is added and stirs It mixes, adjusts pH to 5-6 with dilute hydrochloric acid, stirring and crystallizing cools to 0-5 DEG C of suction filtration, dries to obtain intermediate II；
DMF stirring and dissolving is added in intermediate II, N is added, N- carbonyl dimidazoles, 50-60 DEG C is reacted 2 hours, and intermediate I is added It is warming up to 70-80 DEG C to react 3 hours, evaporated under reduced pressure, after methylene chloride dissolution is added, pours into the mixed solution of pure water and triethylamine Middle stirring liquid separation, separates organic phase, and washing, drying is evaporated, and absolute ethyl alcohol and stirring dissolution is added, and p-methyl benzenesulfonic acid reaction 1 is added Hour, cool down crystallization, filters, dries to obtain intermediate III.
4. the preparation method of intermediate III according to claim 2 or 3, which is characterized in that 4- [2- (2- amino -4,7- bis- Hydrogen -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] molar ratio of benzoic acid and R-CL is 1:1-2.
5. the preparation method of intermediate III according to claim 2 or 3, which is characterized in that 4- [2- (2- amino -4,7- bis- Hydrogen -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] molar ratio of benzoic acid and R-CL is 1:1.5.
6. the preparation method of pemetrexed disodium according to claim 2 or 3, which is characterized in that intermediate II and centre The molar ratio of body I is 1:1-1.8.
7. the preparation method of pemetrexed disodium according to claim 2 or 3, which is characterized in that intermediate II and to first The molar ratio of benzene sulfonic acid is 1:1-1.8.
8. the preparation method of pemetrexed disodium according to claim 2 or 3, which is characterized in that intermediate II and N, N- The molar ratio of carbonyl dimidazoles is 1:1.2-1.8.
9. intermediate III according to claim 1 is preparing the purposes in pemetrexed disodium.
CN201810227832.5A 2018-03-20 2018-03-20 A kind of pemetrexed disodium intermediate and preparation method thereof Pending CN110305136A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1055182A (en) * 1989-12-11 1991-10-09 普林斯顿大学托管委员会 N-(pyrrolo-" 2,3-d " pyrimidin-3-yl acyl group)-glutamic acid derivatives
WO1998008382A1 (en) * 1996-08-30 1998-03-05 Eli Lilly And Company Nonclassical pyrrolo[2,3-d]pyrimidine antifolates
CN102006890A (en) * 2007-12-04 2011-04-06 阿尔尼拉姆医药品有限公司 Targeting lipids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1055182A (en) * 1989-12-11 1991-10-09 普林斯顿大学托管委员会 N-(pyrrolo-" 2,3-d " pyrimidin-3-yl acyl group)-glutamic acid derivatives
WO1998008382A1 (en) * 1996-08-30 1998-03-05 Eli Lilly And Company Nonclassical pyrrolo[2,3-d]pyrimidine antifolates
CN102006890A (en) * 2007-12-04 2011-04-06 阿尔尼拉姆医药品有限公司 Targeting lipids

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