CN110305135A - 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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CN110305135A
CN110305135A CN201810227817.0A CN201810227817A CN110305135A CN 110305135 A CN110305135 A CN 110305135A CN 201810227817 A CN201810227817 A CN 201810227817A CN 110305135 A CN110305135 A CN 110305135A
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pemetrexed disodium
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臧超
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Lunnan Better Pharmaceutical Co ltd
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    • 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
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Abstract

The invention belongs to medical synthesis technical fields, and in particular to a kind of pemetrexed disodium intermediate II -1 and preparation method thereof.With 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid for starting material, acylation reaction occurs in acetic acid, acetic anhydride, by handling to obtain intermediate II -1 after having reacted.Preparing for intermediate II -1 of the present invention is fairly simple; the reaction for be protected from itself to amino generates impurity V, while preventing the unstable oxidation stain conditions of problems occurred during the reaction of amino mild, 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 medical synthesis technical fields, specifically provide a kind of pemetrexed disodium intermediate 4- [2- (2- second Acylamino- -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid and preparation method thereof.
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.
Pemetrexed does not have compound patent in China, and offshore company has applied for that preparation patent and composition are special in China Benefit, but not yet authorize.As treatment malignant pleural mesothelioma specific medicament and treat the potential drugs of advanced lung cancer, from upper Pursuing for numerous pharmacy corporations has been obtained since city, is had more domestic pharmacy corporations at present and is obtained production official written reply, market prospects It is very good.
The structure of pemetrexed disodium is more complicated, and synthetic route is more, and acknowledged ratio preferably process route is It is starting with 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (II) Raw material obtains pemetrexed disodium after condensation, at salt, hydrolysis with Pidolidone diethyl ester hydrochloride, this route raw material is easy , reaction step is shorter, easy to operate, advantage of lower cost, is suitble to industrialized production.Synthetic route is as follows:
But there are more deficiencies for this process route, are mainly manifested in N- { 4- [2- (2- amino -4,7- dihydro -4- oxygen - 3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl }-Pidolidone diethylester toluene fulfonate (structure such as formula III) starting material Pemedolac used in preparation, reactivity site is more, causes by-product more, it is more difficult to it controls, it is especially miscellaneous The content of matter V (structure such as formula V) is up to 5-10%.To reach quality requirement, it is necessary to refine this intermediate (knot by 2-3 times Structure such as formula III), higher cost lower so as to cause whole yield accounts for the large percentage of entire pemetrexed disodium cost of material.
In order to improve product quality, cost is reduced, we are improved and optimized to synthetic route 1.Purpose will be important Starting material Pemedolac (II) protects exposed amido by amidation process, so as to avoid the life of impurity V At making intermediate not need to be refined, directly progress the next step, yield improves nearly 40%, while shortening reaction week Phase.
Summary of the invention
In order to overcome in the prior art pemetrexed disodium prepare that lower yield, high production cost, unstable, purity is low Problem, the present invention provides a kind of pemetrexed disodium intermediate II -1 and preparation method thereof and the systems of pemetrexed disodium IV Preparation Method.
The technical solution adopted by the present invention is that:
On the one hand, the present invention provides a kind of pemetrexed disodium intermediate IIs -1 and preparation method thereof.
The chemical name of intermediate II -1 are as follows: 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3- D] pyrimidine -5- base) ethyl] benzoic acid, structural formula is as follows:
The preparation method of pemetrexed disodium intermediate II -1, comprising the following steps:
It is with 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid In acetic acid, acetic anhydride acylation reaction occurs for starting material, by handling to obtain intermediate II -1 after having reacted.
Reaction route is as follows:
Specifically, the preparation method of pemetrexed disodium intermediate II -1, 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 acetic acid and be warming up to 30 DEG C of stirring and dissolvings, acetic anhydride is added dropwise, is warming up to 40-50 DEG C of insulation reaction 1 hour, evaporated under reduced pressure acetic acid, Pure water stirring is added, adjusts pH to 5-6 crystallization with 5% sodium hydroxide solution, filters, dry to obtain intermediate II -1.
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 acetic anhydride is 1:1-2, it is furthermore preferred that molar ratio is 1:1.2.
Intermediate I chemical name of the present invention are as follows: Pidolidone diethylester, structural formula are as follows:
Intermediate I the preparation method comprises the following steps: using Pidolidone diethyl ester hydrochloride as starting material, potassium carbonate is deacidification agent, Depickling reaction is carried out by solvent of methylene chloride, obtains light yellow oil intermediate I Pidolidone diethylester.
Synthetic route is as follows:
Another aspect of the present invention additionally provides a kind of preparation method of pemetrexed disodium, comprising the following steps:
Be raw material with intermediate I and intermediate II -1, in N, the effect of N- carbonyl dimidazoles is lower to occur condensation reaction, then with P-methyl benzenesulfonic acid reaction, obtains III -1N- of intermediate { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] Pyrimidine -5- base) ethyl] benzoyl }-Pidolidone diethylester toluene fulfonate, then intermediate III -1 is molten in sodium hydroxide P-methyl benzenesulfonic acid, ester hydrolysis, amide hydrolysis are sloughed in liquid, then obtain pemetrexed disodium at sodium salt.
Synthetic route is as follows:
Specifically, the preparation method of pemetrexed disodium, comprising the following steps:
(1) preparation of intermediate III -1:
DMF stirring and dissolving is added in intermediate II -1, N is added, N- carbonyl dimidazoles, 50-60 DEG C is reacted 2 hours, is added Intermediate I is warming up to 70-80 DEG C and reacts 3 hours, and evaporated under reduced pressure pours into pure water and triethylamine after methylene chloride dissolution is added Liquid separation is stirred in mixed solution, separates organic phase, is washed, and drying is evaporated, and absolute ethyl alcohol and stirring dissolution is added, is added to toluene sulphur Acid reaction 1 hour, cool down crystallization, filters, dries to obtain intermediate III -1；
(2) preparation of pemetrexed disodium:
Intermediate III -1 is mixed with sodium hydroxide solution, complete molten rear 10% hydrochloric acid solution that is added dropwise adjusts pH to 2-3, stirring Crystallization 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 Stirring and crystallizing, heat filter, filtrate are added 50% sodium hydroxide solution crystallization, filter, and vacuum drying obtains pemetrexed disodium.
Preferably, the molar ratio of the preparation method of pemetrexed disodium, intermediate II -1 and intermediate (I) is 1:1-2, more It is preferred that 1:1.2.
Preferably, the molar ratio of the preparation method of pemetrexed disodium, intermediate II -1 and p-methyl benzenesulfonic acid is 1:1-2, More preferable 1:1.2.
Preferably, the molar ratio of the preparation method of pemetrexed disodium, intermediate II -1 and N, N- carbonyl dimidazoles are 1: 1.2-2。
Superiority of the invention is shown:
(1) intermediate II -1 of the present invention prepare it is fairly simple, with 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrole Cough up simultaneously [2,3-d] pyrimidine -5- base) ethyl] benzoic acid be raw material carry out amidation process, in order to amino carry out The reaction for being protected from itself generates impurity V, while preventing the unstable oxidation stain problem occurred during the reaction of amino Mild condition, high income, product is relatively stable, is conducive to actual production.
It (2) is that raw material prepares intermediate III -1 with intermediate I and intermediate II -1, due to-the NH of intermediate II -12By Protection avoids -1 autoreactivity of intermediate II and generates V compound of impurity, the quality and receipts of intermediate III -1 greatly improved Rate, production cost decline to a great extent.
(3) preparing pemetrexed disodium with intermediate III -1 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
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration, It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention It is also contained within the scope of the invention.
Embodiment 1:
The preparation of Pidolidone diethylester:
It weighs Pidolidone diethyl ester hydrochloride (48g 0.2mol) to be added in 500ml four-hole bottle, 120ml pure water is added and stirs It after mixing dissolution, is added 18g carbonic acid nak response 0.5 hour, 100ml methylene chloride is added and stirs liquid separation, water layer uses pure water 80ml again × 3 extractions three times, collect organic phase, are evaporated to obtain product Pidolidone diethylester (molar yield 97.5%, purity after dry 94.3%).
Embodiment 2
4- [2- (2- acetylaminohydroxyphenylarsonic acid 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, and 200ml acetic acid is added and is warming up to 30 DEG C of stirring and dissolvings, acetic anhydride is added dropwise (0.2mol), is warming up to 40 DEG C of insulation reactions 1 hour, evaporated under reduced pressure acetic acid, the stirring of 300ml pure water is added, with 5% hydroxide Sodium solution adjusts pH to 5, stirring and crystallizing 2 hours, cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- acetylaminohydroxyphenylarsonic acid 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- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Mass spectrum [M-H]+=341.3.
1H-NMR:1H NMR(400MHz,D2O) δ:
12.12(s,1H)；8.15 (d, 1H, J=8.20Hz)；8.15 (d, 1H, J=8.20Hz)；7.58 (d, 1H, J= 8.20Hz)；7.58 (d, 1H, J=8.20H z)；7.03 (d, 1H, J=8.26Hz)；7.03 (d, 1H, J=8.26)；6.06(s, 1H)；2.76(m,2H)；2.70(m,2H)；2.34(m,2H)；1.86( s,1H).
13C-NMR:13C NMR(400MHz,D2O) δ: 179.30,169.34,160.08,148.74,148.53,146.68, 130.43,130.43,128.18,128.18,128.91,127.91,117.14,104.97,37.12,29.43,23.10.
Embodiment 3
4- [2- (2- acetylaminohydroxyphenylarsonic acid 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, and 200ml acetic acid is added and is warming up to 30 DEG C of stirring and dissolvings, acetic anhydride is added dropwise (0.4mol), is warming up to 50 DEG C of insulation reactions 1 hour, evaporated under reduced pressure acetic acid, the stirring of 300ml pure water is added, with 5% hydroxide Sodium solution adjusts pH to 6, stirring and crystallizing 2 hours, cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- Dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 96.9%, purity 99.0%).
4- [2- (2- acetylaminohydroxyphenylarsonic acid 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- acetylaminohydroxyphenylarsonic acid 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, and 200ml acetic acid is added and is warming up to 30 DEG C of stirring and dissolvings, acetic anhydride is added dropwise (0.24mol), is warming up to 50 DEG C of insulation reactions 1 hour, evaporated under reduced pressure acetic acid, the stirring of 300ml pure water is added, with 5% hydroxide Sodium solution adjusts pH to 6, stirring and crystallizing 2 hours, cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- Dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 97.1%, purity 99.5%).
4- [2- (2- acetylaminohydroxyphenylarsonic acid 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
N- { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Acyl group }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Sour (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, is added 0.228molN, N- carbonyl dimidazoles, 50 DEG C insulation reaction 2 hours, be added Pidolidone diethylester (0.19mol), be warming up to 70 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 36g 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 87.0%, purity 98.9%, V content of impurity be 0).
N- { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Acyl group }-Pidolidone diethylester toluene fulfonate mass spectrum: [M-H]-=524.5.
1H-NMR:1H NMR(400MHz,(CD3)2SO) δ:
7.80 (d, 1H, J=8.26Hz)；7.80 (d, 1H, J=8.26Hz)；7.55(m,1H),7.55(m,1H)；7.30 (d, 1H, J=8.28Hz)；7.30 (d, 1H, J=8.28Hz)；7.16 (d, 1H, J=7.87Hz)；7.16 (d, 1H, J= 7.87H)；6.52 (d, 1H, J=2.06Hz)；4.43(m,1H)；4.09( m,1H)；4.09(m,1H)；2.93(m,2H)；2.93 (m,2H)；2.44 (t, 2H, J=7.49Hz)；2.29(s,3H)；2.06(m,2H)；1.83 (s,3H)；1.17(m,3H)； 1.17(m,3H)。
13C-NMR(400MHz,(CD3)2SO):δ:172.69,172.32,170.32,167.08,157.74,151.06, 146.20,144. 98,139.11,138.89,131.70,128.80,128.80,128.68,128.68,127.95, 127.95,125.98,125.98,119.53,115. 80,99.48,61.02,60.41,52.45,36.18,27.65, 26.17,23.21,21.26,14.54,14.54。
Embodiment 6
N- { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Acyl group }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Sour (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 is added, N- carbonyl dimidazoles, 60 DEG C insulation reaction 2 hours, be added Pidolidone diethylester (0.38mol), be warming up to 80 DEG C reaction 3 Hour, evaporated under reduced pressure is poured into the mixed solution of 1600ml pure water and 160ml triethylamine after the dissolution of 800ml methylene chloride is added Liquid separation to be stirred, organic phase is separated, pure water 1600ml × 2 wash twice, and drying is evaporated, the dissolution of 500ml absolute ethyl alcohol and stirring is added, The ethanol solution of 72g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state, finishes, back flow reaction 1 hour, cools down Crystallization, filter, dry product (molar yield 88.1%, purity 98.3%, V content of impurity be 0).
N- { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Acyl group }-Pidolidone diethylester toluene fulfonate mass spectrum,1H-NMR、13C-NMR is shown in embodiment 5.
Embodiment 7
N- { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Acyl group }-Pidolidone diethylester toluene fulfonate preparation:
By 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Sour (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 is added, N- carbonyl dimidazoles, 60 DEG C insulation reaction 2 hours, be added Pidolidone diethylester (0.48mol), be warming up to 80 DEG C reaction 3 Hour, evaporated under reduced pressure is poured into the mixed solution of 1600ml pure water and 160ml triethylamine after the dissolution of 800ml methylene chloride is added Liquid separation to be stirred, organic phase is separated, pure water 1600ml × 2 wash twice, and drying is evaporated, the dissolution of 500ml absolute ethyl alcohol and stirring is added, The ethanol solution of 90g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under reflux state, finishes, back flow reaction 1 hour, cools down Crystallization, filter, dry product (molar yield 84.7%, purity 98.6%, V content of impurity be 0).
N- { 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzene first Acyl group }-Pidolidone diethylester toluene fulfonate mass spectrum,1H-NMR、13C-NMR is shown in embodiment 5.
Embodiment 8
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- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl }-Pidolidone two Ethyl 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, 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 DEG C of stirring and dissolvings, with 20% sodium hydroxide Solution adjusts pH to 6 stirring and crystallizings, and heat is filtered, and filtrate is refunded in bottle, and 50% sodium hydroxide solution 24g is added, and stirring is warming up to 50 DEG C, it is stirred to react 1 hour, cools to 0 DEG C, stirring and crystallizing 5 hours, filter, vacuum drying obtains white solid pemetrexed disodium (molar yield 81.5%, purity 99.85%).
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.
Embodiment 9
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- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl }-Pidolidone two Ethyl ester toluene fulfonate (112.7g 0.16mol) stirring and dissolving, complete molten rear 10% hydrochloric acid solution that is added dropwise adjust pH to 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 60 DEG C of stirring and dissolvings, with 20% sodium hydroxide Solution adjusts PH to 7 stirring and crystallizings, and heat is filtered, and filtrate is refunded in bottle, and 50% sodium hydroxide solution 24g is added, and stirring is warming up to 50 DEG C, it is stirred to react 1 hour, cools to 0 DEG C, stirring and crystallizing 5 hours, filter, vacuum drying obtains white solid (molar yield 82.3%, purity 99.86%).
Mass spectrum, 1H-NMR, 13C-NMR of pemetrexed disodium are shown in embodiment 8.
Comparative example 1
4- [2- (2- acetylaminohydroxyphenylarsonic acid 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, and 200ml acetic acid is added and is warming up to 30 DEG C of stirring and dissolvings, acetic anhydride is added dropwise (0.5mol), is warming up to 50 DEG C of insulation reactions 1 hour, evaporated under reduced pressure acetic acid, the stirring of 300ml pure water is added, with 5% hydroxide Sodium solution adjusts pH to 6, stirring and crystallizing 2 hours, cools to 0-5 DEG C of suction filtration, dries to obtain product 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- Dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid (molar yield 93.4%, purity 97.6%).
4- [2- (2- acetylaminohydroxyphenylarsonic acid 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
Comparative example 2
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 is added, N- carbonyl dimidazoles, 60 DEG C insulation reaction 2 hours, be added Pidolidone diethylester (0.38mol), it is 3 small to be warming up to 80 DEG C of reactions When, 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 is mixed, organic phase is separated, pure water 1600ml × 2 wash twice, and drying is evaporated, and the dissolution of 500ml absolute ethyl alcohol and stirring is added, returns The ethanol solution of 72g mono- water p-methyl benzenesulfonic acid and 200ml is added dropwise under stream mode, finishes, back flow reaction 1 hour, cooling analysis Crystalline substance, 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 Hour, 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 obtain N- (4- [2- (2- amino -4,7- dihydro -4- oxo -3H- pyrrolo- [2,3-d] Pyrimidine -5- base) ethyl] benzoyl)-Pidolidone.Step gained N- (4- [2- (2- amino -4,7- bis- on being added in four-hole bottle Hydrogen -4- oxo -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoyl)-Pidolidone and 200ml0.5mol/L hydrogen-oxygen Change sodium, stir 1 hour, cross and filter out insoluble matter, obtain clear solution, is 8 with 0.5mol/L salt acid for adjusting pH, acquired solution is heated to 50 DEG C, stir 30 minutes, be down to room temperature, be added 300ml ethyl alcohol and dimethyl sulfoxide mixed solvent (volume ratio 10: 1.8) it, stirs 10 minutes, is stirred 2 hours at 0 DEG C, filtered, the mixed solvent of solid 60ml ethyl alcohol and dimethyl sulfoxide (volume ratio 10:1.8) washing, 50 DEG C obtain pemetrexed disodium, yield 60.9%, purity 97.5% in vacuum drying 5 hours.
Mass spectrum, 1H-NMR, 13C-NMR of pemetrexed disodium are shown in embodiment 8.

Claims (10)

1. a kind of pemetrexed disodium intermediate II -1, chemical name are as follows: 4- [2- (2- acetylaminohydroxyphenylarsonic acid 4,7- dihydro -4- oxygen - 3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid, structure is as follows:
2. a kind of preparation method of pemetrexed disodium intermediate II -1 described in claim 1, which is characterized in that including following Step:
It is starting with 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid In acetic acid, acetic anhydride acylation reaction occurs for material, by handling to obtain intermediate II -1 after having reacted.
3. the preparation method of pemetrexed disodium intermediate II -1 according to claim 2, which is characterized in that including following Step:
Second is added in 4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid Sour stirring and dissolving, be added dropwise acetic anhydride, 40-50 DEG C insulation reaction 1 hour, evaporated under reduced pressure acetic acid, be added pure water stirring, with 5% hydrogen Sodium hydroxide solution adjusts pH to 5-6, and crystallization filters, dries to obtain intermediate II -1.
4. the preparation method of pemetrexed disodium intermediate II -1 according to claim 2 or 3, which is characterized in that
4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid and acetic anhydride Molar ratio be 1:1-2.
5. the preparation method of pemetrexed disodium intermediate II -1 according to claim 2 or 3, which is characterized in that
4- [2- (2- amino -4,7- dihydro -4- oxygen -3H- pyrrolo- [2,3-d] pyrimidine -5- base) ethyl] benzoic acid and acetic anhydride Molar ratio be 1:1.2.
6. a kind of method that pemetrexed disodium intermediate II -1 is used to prepare pemetrexed disodium described in claim 1, special Sign is, comprising the following steps:
It is raw material with intermediate I Pidolidone diethylester and intermediate II -1, in N, the effect of N- carbonyl dimidazoles is lower to be condensed Reaction, then reacts with p-methyl benzenesulfonic acid, obtains intermediate III -1, then intermediate III -1 is sloughed in sodium hydroxide solution to first Benzene sulfonic acid, ester hydrolysis, amide hydrolysis, then obtain pemetrexed disodium at sodium salt.
7. preparing the method for pemetrexed disodium according to claim 6, which comprises the following steps:
(1) preparation of intermediate III -1:
DMF stirring and dissolving is added in intermediate II -1, N is added, N- carbonyl dimidazoles, 50-60 DEG C is reacted 2 hours, is added intermediate Body I is warming up to 70-80 DEG C and reacts 3 hours, and evaporated under reduced pressure pours into the mixing of pure water and triethylamine after methylene chloride dissolution is added Liquid separation is stirred in solution, separates organic phase, is washed, and 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 -1；
(2) preparation of pemetrexed disodium:
Intermediate III -1 is mixed with sodium hydroxide solution, 10% hydrochloric acid solution is added dropwise after intermediate III -1 all dissolution and adjusts PH to 2-3, stirring and crystallizing filter, and filter cake is added dehydrated alcohol and is warming up to 50-60 DEG C of stirring and dissolving, molten with 20% sodium hydroxide Liquid adjusts pH to 6-7 stirring and crystallizing, and heat is filtered, and filtrate is refunded in bottle, and 50% sodium hydroxide solution crystallization is added, and is filtered, and vacuum is dry It is dry, obtain pemetrexed disodium.
8. preparing the method for pemetrexed disodium described according to claim 6 or 7, which is characterized in that intermediate II -1 and centre The molar ratio of body I is 1:1-2.
9. preparing the method for pemetrexed disodium described according to claim 6 or 7, which is characterized in that intermediate II -1 and to first The molar ratio of benzene sulfonic acid is 1:1-2.
10. preparing the method for pemetrexed disodium described according to claim 6 or 7, which is characterized in that intermediate II -1 and N, N- The molar ratio of carbonyl dimidazoles is 1:1.2-2.
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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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