CN103265428B - Method for preparing 4-[(3-halogenate-4-oxo) butyl] benzoic acid - Google Patents
Method for preparing 4-[(3-halogenate-4-oxo) butyl] benzoic acid Download PDFInfo
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Abstract
The invention discloses a method for preparing a medical intermediate 4-(3-halogenate-4-oxo butyl) benzoic acid (I). The method comprises the following steps of: carrying out grignard reaction on 4-(2-halogenated ethyl) benzoic acid (II) and glyoxal dialkyl acetal (III) to generate 4-[(4,4-dimethoxy-3-hydroxy) butyl] benzoic acid (IV); and carrying out halogenation and deprotection on the intermediate (IV) to obtain 4-[(3-halogenate-4-oxo) butyl] benzoic acid (I), wherein the obtained 4-[(3-halogenate-4-oxo) butyl] benzoic acid (I) is condensed with 2,4-diamido-6-hydroxypyrmidine (V) to prepare a key intermediate 4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo[2,3-d] pyrimidine-5-yl] benzoic acid (VI) which is used for synthesizing an antineoplastic drug pemetrexed. The preparation method is available in material, concise in technology, convenient to purify, high in quality, and suitable for industrialized production.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and intermediate preparing technical field, particularly a kind of 4-[(3-halo-4-oxo) butyl] benzoic preparation method.
Background technology
Pemetrexed disodium (Pemetrexed disodium) is a kind of novel many target position folic acid retarding agent of the pyrroles's of containing pyrimidine group.Can block needed plurality of enzymes in cancer cells division and hyperplasia process, thereby reach antineoplastic effect.This medicine, by the exploitation of Lilly (EliLilly) company, in the Initial Public Offering of the 2004 Nian U.S., is approved for and Cisplatin treatment malignant pleural mesothelioma and nonsmall-cell lung cancer, and commodity are called Alimta (Alimta).In December, 2005, this medicine was in Discussion on Chinese Listed, and the indication of approval is malignant pleural mesothelioma.
The active pharmaceutical ingredients of pemetrexed disodium is pemetrexed, chemistry N-[4-[2-by name (2-amino-4,7-dihydro 4-4-oxygen-1H-pyrroles [2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-Pidolidone, its structural formula is as follows:
Relevant pemetrexed and the existing more report of intermediate preparation, wherein that (2-amino-4 by first synthetic key intermediate 4-[2-mostly, 7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] phenylformic acid (VI, hereinafter to be referred as the U.S. phenylformic acid of training), then make pemetrexed and disodium salt thereof with the condensation of Pidolidone diethyl ester.And the preparation of training U.S. phenylformic acid (VI) is by 4-[(3-halo-4-oxo mostly) butyl] phenylformic acid (I) or ester (VIII) and 2,4-diamino-6-hydroxy pyrimidine (V) condensation and making.
No. US6066732nd, United States Patent (USP), No. US6013828 and No. US6262262 and No. CN1271338th, Chinese patent and CN101591247 etc. have reported a kind of 3-of utilization butene-1-ol and iodine (or bromine) methyl benzoate (or ethyl ester) have been carried out to Heck reaction, prepare compound 4-(4-alkoxycarbonylphenyl)-1-butyraldehyde (VII), compound (VII) obtains 4-[(3-halo-4-oxo by-sulfinic acid to the addition of aldehyde and bromine substitution reaction) butyl] benzoic ether (VIII), compound (VIII) obtains training U.S. phenylformic acid (VI) through cyclization and hydrolysis, the step of its whole reaction is as shown in the formula expression:
The method step is succinct, but because 3-butene-1-ol be difficult to obtain, in Heck reaction, also needs to use expensive palladium catalyst and phase-transfer catalyst, reacts more difficult control and yield not high, so limited the industrialization of this route.
In order to improve 3-butene-1-ol, be difficult to the cost pressure that obtains and bring thus, have researchist that the synthetic route that a kind of 3-of utilization butyne-1-ol is starting raw material is provided.This route is to carry out Heck reaction by 3-butyne-1-ol with to iodine (or bromine) methyl benzoate (or ethyl ester), generate 4-(2-alkynyl-4-butanols) benzoic ether, addition and bromine substitution reaction by shortening, Jones oxidation,-sulfinic acid obtains the bromo-4-oxo of 4-[(3-successively again) butyl] benzoic ether (VIII), follow-up and above-mentioned route is consistent, finally obtain pemetrexed intermediate and train U.S. phenylformic acid, its reactions steps is as shown in the formula expression:
Although this route substitutes 3-butene-1-ol by 3-butyne-1-ol, raw material more easily obtains and cost declines on year-on-year basis to some extent, but due to equally will be through the Heck reaction of palladium catalysis, and follow-uply also will increase the steps such as catalytic hydrogenation and oxidation, make grasping more loaded down with trivial details, be not suitable for suitability for industrialized production.
Equally, in order to solve the raw materials such as 3-butene-1-ol, be difficult to the problem obtaining, No. US6066732nd, patent, No. CN1827604, No. CN1800169 and CN1778797 etc. have selected another reaction scheme: with the vinylcarbinol being easy to get, replace 3-butene-1-ol and iodine (or bromine) methyl benzoate (or ethyl ester) is carried out to Heck react, generate 4-(alkoxyl formyl) phenylpropyl aldehyde, addition and hydroxyl elimination reaction by Nitromethane 99Min. obtains intermediate 1-nitro-4-(4-alkoxyl formyl phenyl)-2-butanols (IX) and 1-nitro-4-(4-alkoxyl formyl phenyl)-2-butylene (X) successively again, this intermediate (X) and 2, 6-diamino-4-hydroxy pyrimidine (V) condensation, obtain 1-nitro-2-(2, 6-diamino-4 (3H)-oxo pyrimidine-5-yl)-4-(4-alkoxyl formyl phenyl) butane (XI), through ring-closure reaction under base catalysis and hydrolysis reaction, obtain pemetrexed intermediate again and train U.S. phenylformic acid (VI), its reactions steps is shown below:
This route has solved raw material sources problem, and cost is declined to some extent.But due to follow-up condensation and ring-closure reaction selectivity poor, easily produce positional isomers impurity, so affected industrialized use.
Chinese patent has reported that take chlorine propionic aldehyde prepares the U.S. benzoic operational path of intermediate training as starting raw material for No. CN101085775: with the chlorine propionic aldehyde of aldehyde radical protection and p-methylbenzoic acid under the effect of n-Butyl Lithium; carry out alkylated reaction, obtain para Toluic Acid's butyraldehyde derivatives.Esterification and deprotection by formic acid generate 4-(4-alkoxycarbonylphenyl)-1-butyraldehyde (VII).Same method, can prepare training U.S. phenylformic acid (VI) by intermediate (VII) through intermediate (VIII).This route raw material is easy to get, and step is succinct, but the first step alkylated reaction need to be used the organometallic reagents such as n-Butyl Lithium, harsher to conversion unit and environmental requirement, and yield is not high.
The operational path that maleic anhydride is starting raw material of take of < < organic chemistry > > 2006 (4): 546-550 report comprises: take benzene and maleic anhydride as classical Fu-Ke (Friedel-Crafts) acylation reaction occurs raw material under Using Aluminium Trichloride as Catalyst, generate 3-benzoyl propionic acid.By carbonyl reduction, obtain 4-phenylbutyrate; by esterification, secondary Fu-Ke (Friedel-Crafts) acylations and lithium aluminium hydride reduction, obtain 4-(4-ethoxy acetyl) phenyl butanols again; through PCC, be oxidized to obtain intermediate 4-(4-alkoxycarbonylphenyl)-1-butyraldehyde (VII), also identical with aforesaid method to the method for training U.S. phenylformic acid (VI) by intermediate (VII).This reaction scheme raw material is easy to get; but step is various,, through twice Fu-Ke (Friedel-Crafts) acylation reaction, twice esterification, a lithium aluminium hydride reduction and a PCC oxidizing reaction, just can obtain intermediate (VII); total recovery is low, is unfavorable for industrialization.
In addition; reported for work for No. CN102827168 synthetic method of the U.S. phenylformic acid of a kind of training (VI) of Chinese patent; the method be the industrial raw material benzene being easy to get be most starting raw material; through the Friedel-Crafts on phenyl ring and friedel-crafts acylation, generate 4-(4-butanols) benzoic ether; through peroxidation and bromo, obtain intermediate 4-(4-alkoxycarbonylphenyl)-1-butyraldehyde (VII) again, with method, also can make training U.S. phenylformic acid (VI).The method advantage is that cost is low, step is few, but because twice Friedel-Crafts reaction yield is medium, has still affected industrialization speed.
Summary of the invention
The object of the invention is to for defect of the prior art, a kind of improved 4-[(3-halo-4-oxo is provided) butyl] preparation method of phenylformic acid (I), this preparation method has advantages of that raw material is easy to get and technique is succinct, and the U.S. phenylformic acid purity of the training that utilizes intermediate (I) prepared by the method to prepare is high, good stability and with low cost.
For achieving the above object, the present invention has mainly adopted following technical scheme: a kind of 4-[(3-halo-4-oxo) butyl] preparation method of phenylformic acid (I),
Described preparation method comprises the steps: that 4-(2-halogenated ethyl) phenylformic acid (II) and oxalic dialdehyde dialkyl group monoacetal (III) grignard reaction occur and generate 4-[(4; 4-dimethoxy-3-hydroxyl) butyl) phenylformic acid (IV); 4-[(4,4-dimethoxy-3-hydroxyl) butyl) phenylformic acid (IV) makes 4-[(3-halo-4-oxo through halogenating reaction and deprotection) butyl] phenylformic acid (I).
In addition, the present invention also proposes following attached technical scheme:
Halogen X in described compound (I) is fluorine, chlorine, bromine or iodine, preferably bromine.
In described raw material oxalic dialdehyde dialkyl group monoacetal (III), alkyl R is the phenyl of methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, phenyl or replacement, preferable methyl.
The raw material 4-of described grignard reaction (2-halogenated ethyl) phenylformic acid (II) is 1 with the molar ratio of oxalic dialdehyde dialkyl group monoacetal (III): 08-1.6, preferably 1: 1.
The solvent of described grignard reaction is benzene, toluene, ether, isopropyl ether, glycol dimethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran (THF) or they both mixed solvents, the preferably mixed solvent (volume ratio is 1: 1) of tetrahydrofuran (THF), methyl tert-butyl ether or tetrahydrofuran (THF) and methyl tert-butyl ether arbitrarily.
The halogenating agent of described halogenating reaction is elemental halogen, hydrogen halide, metal halide, Phosphorates phosphorus Halides, halogenation oxygen phosphorus, halocarbon or thionyl chloride, preferably phosphorus tribromide.
The acid binding agent of described halogenating reaction is triethylamine, diisopropylamine, pyridine, salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium tert.-butoxide, preferably triethylamine or pyridine.
Described 4-(3-halo-4-oxo-1-butyl) phenylformic acid (I) and 2,4-diamino-6-hydroxy pyrimidine (V) direct polycondensation also can make for the synthetic key intermediate of antitumour drug pemetrexed disodium (being called for short the U.S. phenylformic acid of training) 4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] phenylformic acid (VI).
Than prior art, the preparation method of pemetrexed intermediate 4-involved in the present invention (3-halo-4-oxo-1-butyl) phenylformic acid (I), have that raw material is easy to get, technique is succinct, cost is lower and the feature such as quality controllable, and the U.S. phenylformic acid purity of the training that utilizes intermediate (I) prepared by the method to prepare is high, good stability and with low cost, so be beneficial to the suitability for industrialized production of this bulk drug, promote the development of its economic technology.
Embodiment
Below in conjunction with several preferred embodiments, technical solution of the present invention is further non-limitingly described in detail.
Embodiment mono-:
Under dry and nitrogen atmosphere, in there-necked flask, add 4-(2-bromotrifluoromethane) phenylformic acid (II) (4.54g, 20mmol), magnesium chips (1.44g, 60mmol) and tetrahydrofuran solution 50mL, with iodine, cause, Grignard reagent is made in 45 ℃ of reactions for 5 hours.Be cooled to 0 ℃, under vigorous stirring, drip the solution that glyoxal dimethyl base monoacetal (III) (2.08g, 20mmol) and methyl tert-butyl ether 50mL form.Slowly be warming up to room temperature, stirring reaction 12 hours, TLC detection reaction finishes.Add saturated ammonium chloride solution to carry out cancellation reaction, with dichloromethane extraction, anhydrous sodium sulfate drying.Decompression and solvent recovery, obtains yellow oil 4-[(4,4-dimethoxy-3-hydroxyl) butyl) phenylformic acid (IV) 3.85g, yield 75.8%.
Embodiment bis-:
In there-necked flask, add 4-[(4,4-dimethoxy-3-hydroxyl) butyl) phenylformic acid (IV) (2.54g, 10mmol), pyridine (2.4g, 30mmol) and methylene dichloride 50mL.Be cooled to 0 ℃, under stirring, drip phosphorus tribromide (5.4g, 20mmol), drip and finish, room temperature reaction 4 hours, TLC detection reaction finishes.Solids removed by filtration, mother liquor is water and salt solution washing successively, vacuum distillation recovered solvent.Resistates adds trifluoracetic acid, and room temperature reaction 10 hours adds the shrend reaction of going out, and toluene extraction, concentrated recrystallization again obtain faint yellow solid 4-[(3-halo-4-oxo) butyl] phenylformic acid (I) 2.18g, yield is 80.7%.
Embodiment tri-:
In reaction flask, add 4-[(3-halo-4-oxo) butyl] phenylformic acid (I) (1.35g, 5mmol), 2,4-diamino-6-hydroxy pyrimidine (VI) (0.77g, 6mmol), first alcohol and water (1: 1) mixed solvent 25mL, be stirred to down and add sodium-acetate (0.82g, 10mmol), be warming up to 45 ℃, react 5 hours, TLC detection reaction completes.Cooling, have solid to separate out, with acetone recrystallization, obtaining off-white color solid 4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] phenylformic acid (trains U.S. phenylformic acid, VI) 1.2g, yield 80.5%.
It is pointed out that above-described embodiment is only explanation technical conceive of the present invention and feature, its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (6)
1. 4-[(3-halo-4-oxo) butyl] preparation method of phenylformic acid (I),
It is characterized in that described preparation method comprises the steps:
There is grignard reaction with oxalic dialdehyde dialkyl group monoacetal (III) and generate 4-[(4 in 4-(2-halogenated ethyl) phenylformic acid (II), 4-dialkoxy-3-hydroxyl) butyl) phenylformic acid (IV), described 4-[(4,4-dialkoxy-3-hydroxyl) butyl) phenylformic acid (IV) makes 4-[(3-halo-4-oxo through halogenating reaction and deprotection) butyl] phenylformic acid (I), wherein said 4-[(3-halo-4-oxo) butyl] halogen X in phenylformic acid (I) is fluorine, chlorine, bromine or iodine, and X1 in starting raw material 4-(2-halogenated ethyl) phenylformic acid (II) is halogen; And alkyl R is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl in described oxalic dialdehyde dialkyl group monoacetal (III).
2. 4-[(3-halo-4-oxo as claimed in claim 1) butyl] preparation method of phenylformic acid (I), it is characterized in that: the raw material 4-of described grignard reaction (2-halogenated ethyl) phenylformic acid (II) is 1:08-1.6 with the molar ratio of oxalic dialdehyde dialkyl group monoacetal (III).
3. 4-[(3-halo-4-oxo as claimed in claim 1) butyl] preparation method of phenylformic acid (I), it is characterized in that: the solvent of described grignard reaction is benzene, toluene, ether, isopropyl ether, glycol dimethyl ether, dioxane or tetrahydrofuran (THF).
4. 4-[(3-halo-4-oxo as claimed in claim 1) butyl] preparation method of phenylformic acid (I), it is characterized in that: the halogenating agent of described halogenating reaction is elemental halogen, hydrogen halide, metal halide, Phosphorates phosphorus Halides, halogenation oxygen phosphorus, halocarbon or thionyl chloride.
5. 4-[(3-halo-4-oxo as claimed in claim 1) butyl] preparation method of phenylformic acid (I), it is characterized in that: the acid binding agent of described halogenating reaction is triethylamine, diisopropylamine, pyridine, salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium tert.-butoxide.
6. 4-[(3-halo-4-oxo as claimed in claim 1) butyl] preparation method of phenylformic acid (I), it is characterized in that: described 4-[(3-halo-4-oxo) butyl] phenylformic acid (I) and 2, condensation reaction occurs 4-diamino-6-hydroxy pyrimidine (V) can make (the 2-amino-4 for the synthetic key intermediate 4-[2-of antitumour drug pemetrexed disodium, 7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] phenylformic acid (VI)
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| CN107628947B (en) * | 2017-09-14 | 2020-07-28 | 浙江工业大学 | A kind of preparation method of pemetrexed disodium key intermediate |
| CN109232579B (en) * | 2018-11-06 | 2021-07-23 | 淮海工学院 | A kind of method for synthesizing pemetrexed intermediate pemetrexed benzoic acid |
| CN111302930B (en) * | 2020-03-12 | 2023-11-07 | 湖南复瑞生物医药技术有限责任公司 | A kind of preparation method of p-phenylbutoxybenzoic acid |
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| TWI374886B (en) * | 2006-08-14 | 2012-10-21 | Sicor Inc | Processes for preparing intermediates of pemetrexed |
| CN100509814C (en) * | 2007-07-06 | 2009-07-08 | 吴洪流 | Pemetrexed intermediate and preparation method thereof |
| US9174991B2 (en) * | 2009-11-24 | 2015-11-03 | Azad Pharmaceutical Ingredients Ag | Crystalline form of pemetrexed disodium |
| EP2654795B1 (en) * | 2010-12-21 | 2018-03-07 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of pemetrexed-based compounds |
| CN102827168A (en) * | 2012-09-24 | 2012-12-19 | 苏州立新制药有限公司 | Preparation method of pemetrexed intermediate |
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