CN106749270B - A kind of synthetic method of anti-folic acid small-molecule chemical drug - Google Patents
A kind of synthetic method of anti-folic acid small-molecule chemical drug Download PDFInfo
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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 present invention relates to a kind of synthetic methods of anti-folic acid small-molecule chemical drug.Specifically, the invention discloses a kind of new preparation process of pemetrexed.This method is by first reacting compound (II) with ethyl cyanoacetate (III); gained compound (IV) and guanidine (V) cyclization generate pyrimidines (VI); last cyclization and hydrolysis obtain target product N- { 4- { 2- (2- amino -4; 7- dihydro -4- oxo -3H- pyrrolo- (2,3-d) pyrimidine -5- base) ethyl } benzoyl }-Pidolidone (I).The reaction has reaction condition mild, and process efficiency is high, advantages of environment protection, therefore is suitable for industrialized production.
Description
Technical field
The invention belongs to chemical pharmaceutical technology fields, in particular it relates to which a kind of treat non-small cell lung cancer and evil
The pemetrexed preparation method of property mesothelioma of pleura；More particularly it relates to a kind of preparation N- { 4- { 2- of high effect cleaning
(2- amino -4,7- dihydro -4- oxo -3H- pyrrolo- (2,3-d) pyrimidine -5- base) ethyl } benzoyl }-Pidolidone (I)
New method.
Background technique
Pemetrexed (Anagrelide AG) is one kind using pyrimido pyrroles as the anti-folic acid small-molecule chemical medicine of motherboard
Object, the medicine inhibit the duplication of cancer cell, to control tumour by the normal metabolic processes of the intracellular folate-dependant of destruction
Growth.Its main function target spot is thymidylate synthetase (TS), dihyrofolate reductase (DHFR), glycinamide ribonucleotide turn
Formylase (GARFT) influences the synthesis of purine and pyrimidine by the inhibition on these key enzymes, and then inhibits DNA synthesis.It is clinical
Research have shown that pemetrexed list medicine can to non-small cell lung cancer, malignant pleural mesothelioma, head and neck neoplasm, gastric cancer, bladder cancer,
The advantages that tumours such as cervical carcinoma and cancer of pancreas have therapeutic effect, have antitumor spectra wide, significant effect, Small side effects.U.S.'s gift
The pemetrexed disodium for carrying out company's exploitation is listed in acquisition FDA approval in 2004 and in the U.S., for treating malignant pleural mesothelium
Tumor and non-small cell lung cancer.The structural formula of pemetrexed is as follows:
According to document report, the synthetic route of pemetrexed (I) is prepared just like following:
Using 4- iodo-benzoic acid as starting material in the patent CN101293854B that route one: Lin Dong et al. is delivered, pass through acyl
Chlorination, amidation, Heck coupling reaction, aldehyde radical protection, hydrolysis is halogenated, and totally seven steps synthesize target product pemetrexed to cyclization.It should
Synthetic route starting material is simple, but complex for operation step, and using the biggish thionyl chloride of pollution make reaction reagent and
Solvent, and using heavy metal catalysts such as palladium chloride or palladium acetates, route is longer, substantially reduces total recovery, and route is as follows:
The patent US6066732 that route two: Taylar etc. is delivered is reported is with 4- iodo ethyl benzoate and propenyl
Beginning raw material is obtained by Heck coupling reaction, Henry reaction, elimination reaction, addition reaction and Nef reaction cyclization and hydrolysis
Pemedolac, the route total recovery only have 32.9%, and prepare pemetrexed and also need further amide and hydrolysis.
Route three: in the patent CN1271338 that barye top grade is delivered, it was recently reported that use Pemedolac (Pemetrexed
Acid it is) raw material, prepares pemetrexed ester with glutamate diethyl ester condensation, then hydrolyze again, obtain the preparation side of pemetrexed
Method, the route is fairly simple, but Pemedolac is difficult to obtain.The route steps are as follows:
Route four: Guo Zhixiong etc. has been delivered in " organic chemistry " (2006,26 (4): 546-550) using simple benzene as original
Material prepares 3- benzoyl propionic acid, is then restored, is esterified, secondary Fu by carrying out friedel-crafts acylation with maleic anhydride
Gram reaction, secondary reduction, oxidation, bromination, cyclisation, hydrolysis etc. series reactions synthesize pemetrexed intermediate Pemedolac, the road
Line raw material is simple, but uses the biggish lithium aluminium hydride reduction of risk as reducing agent, and route is longer, and overall yield is lower, unfavorable
In industrialized production.
To sum up described in document, there are various shortcomings about the process route for preparing pemetrexed at present, therefore,
Need to study it is a kind of can both reduce production cost, provide yield and purity, environmental-friendly process route solves pemetrexed
Technological problems.
Summary of the invention
The object of the present invention is to provide a kind of novel pemetrexed preparation methods.
First aspect present invention, which provides, a kind of prepares N- { 4- { 2- (2- amino -4,7- dihydro -4- oxo -3H- pyrrolo-
(2,3-d) pyrimidine -5- base) ethyl benzoyl-Pidolidone (I) method, comprising steps of
(1) preparation of compound (IV):
Compound (II) and compound (III) are uniformly mixed, reacted under condition of no solvent by grinding, thus shape
At compound (IV)；
(2) preparation of compound (VI)
Compound (IV) and compound (V) are uniformly mixed, reacted under condition of no solvent by grinding, to be formed
Compound (VI)；
(3) preparation of compound (I):
In atent solvent, in the presence of a catalyst, compound (VI) is subjected to cyclization and hydrolysis, to form training
Beautiful Qu Sai (I).
In another preferred example, in step (1), the temperature of the reaction is 0~80 DEG C；Preferably 10~50 DEG C.
In another preferred example, in step (2), the temperature of the reaction is 0~80 DEG C, preferably 10~50 DEG C.
In another preferred example, in step (3), the inactive reagents are selected from the group: water, ethyl acetate, methanol, second
Alcohol, isopropanol, methylene chloride, tetrahydrofuran, toluene, dimethylbenzene, or combinations thereof.
In another preferred example, in step (3), the temperature of the reaction is -20~80 DEG C.
In another preferred example, in step (3), the temperature of the reaction is -20~60 DEG C, preferably -10~50 DEG C.
In another preferred example, the step (3) comprising steps of
Compound (VI) in the presence of base catalyst, is carried out first set reaction, thus shape in atent solvent by (3-1)
At a reaction mixture；
(3-2) in presence of an acid catalyst, the reaction mixture that above-mentioned steps are obtained carries out the second secondary response, thus shape
At pemetrexed (I).
In another preferred example, in step (3-1), the base catalyst is selected from the group: potassium carbonate, sodium carbonate, carbonic acid
Hydrogen sodium, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, or combinations thereof.
In another preferred example, in step (3-1), the first set reaction carries out at 30~55 DEG C.
In another preferred example, in step (3-1), the first set reaction carries out at 40~45 DEG C.
In another preferred example, in step (3-1), the first set reaction is carried out 1-4 hours；It is preferred that 1-3 hours.
It in another preferred example, further include by reaction mixture silicon after first set reaction in step (3-1)
Glue filtering.
In another preferred example, the silica gel is 100-200 purpose.
In another preferred example, in step (3-2), the acid catalyst is selected from the group: sulfuric acid, hydrochloric acid, nitric acid, vinegar
Acid, formic acid, or combinations thereof.
In another preferred example, in step (3-2), second secondary response carries out at -10~15 DEG C.
In another preferred example, in step (3-2), second secondary response carries out at 0~5 DEG C.
In another preferred example, in step (3-2), second secondary response is carried out 0.5-4 hours；It is preferred that 0.5-2 is small
When.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
The present inventor after extensive and in-depth study, has been surprisingly found that a kind of novel pemetrexed preparation method.The road
Line has the advantages that easy to operate, production cost is low, environmental-friendly, total recovery height and purity is high, is suitble to industrialized production.Herein
On the basis of, inventor completes the present invention.
Preparation method
The present invention provides a kind of new preparation method of pemetrexed,
Comprising steps of
(1) preparation of compound (IV):
Compound (II) and compound (III) are uniformly mixed, reacted under condition of no solvent by grinding, thus shape
At compound (IV)；
In another preferred example, in step (1), the temperature of the reaction is 0~80 DEG C；Preferably 10~50 DEG C.
In another preferred example, in step (1), after reaction, obtained reaction mixture is handled as follows: first
First reaction mixture is dissolved in organic solvent, and with liquid scrubbing selected from the group below: water, saturated salt solution, or combinations thereof；So
Afterwards by organic phase concentration, drying.
(2) preparation of compound (VI)
Compound (IV) and compound (V) are uniformly mixed, reacted under condition of no solvent by grinding, to be formed
Compound (VI)；
In another preferred example, in step (2), the temperature of the reaction is 0~80 DEG C, preferably 10~50 DEG C.
In another preferred example, in step (2), after reaction, obtained reaction mixture is handled as follows: first
First reaction mixture is dissolved in organic solvent, and with liquid scrubbing selected from the group below: water, saturated salt solution, saturated sodium carbonate
Solution, or combinations thereof；Then by organic phase concentration, drying.
(3) preparation of compound (I):
In atent solvent, in the presence of a catalyst, compound (VI) is subjected to cyclization and hydrolysis, thus formed
It closes object (I) (i.e. pemetrexed).
In another preferred example, in step (3), the inactive reagents are selected from the group: water, ethyl acetate, methanol, second
Alcohol, isopropanol, methylene chloride, tetrahydrofuran, toluene, dimethylbenzene, or combinations thereof.
In another preferred example, in step (3), the temperature of the reaction is -20~80 DEG C.
In another preferred example, in step (3), the temperature of the reaction is -20~60 DEG C, preferably -10~50 DEG C.
In another preferred example, the step (3) comprising steps of
Compound (VI) in the presence of base catalyst, is carried out first set reaction, thus shape in atent solvent by (3-1)
At a reaction mixture；
(3-2) in presence of an acid catalyst, the reaction mixture that above-mentioned steps are obtained carries out the second secondary response, thus shape
At compound (I).
In another preferred example, in step (3-1), the inactive reagents are selected from the group: water, ethyl acetate, methanol, second
Alcohol, isopropanol, methylene chloride, tetrahydrofuran, toluene, dimethylbenzene, or combinations thereof.
In another preferred example, in step (3-1), the base catalyst is selected from the group: potassium carbonate, sodium carbonate, carbonic acid
Hydrogen sodium, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, or combinations thereof.
In another preferred example, in step (3-1), the first set reaction carries out at 30~55 DEG C.
In another preferred example, in step (3-1), the first set reaction carries out at 40~45 DEG C.
In another preferred example, in step (3-1), the first set reaction is carried out 1-4 hours.
In another preferred example, in step (3-1), the first set reaction is carried out 1-3 hours.
It in another preferred example, further include by reaction mixture silicon after first set reaction in step (3-1)
Glue filtering.
In another preferred example, in step (3-1), after first set reaction, silica gel is added in the reactive mixture
After stirring, filtering.
In another preferred example, the stirring carries out 10-20 minutes, preferably 15 minutes.
In another preferred example, the silica gel is 100-200 purpose.
In step (3-1), the yield and purity of final products are helped to improve by control temperature, with silica gel treatment etc.,
And help to simplify the post-processing step of product.
In another preferred example, in step (3-2), the acid catalyst is selected from the group: sulfuric acid, hydrochloric acid, nitric acid, vinegar
Acid, formic acid, or combinations thereof.
In another preferred example, in step (3-2), second secondary response carries out at -10~15 DEG C.
In another preferred example, in step (3-2), second secondary response carries out at 0~5 DEG C.
In another preferred example, in step (3-2), second secondary response is carried out 0.5-4 hours.
In another preferred example, in step (3-2), second secondary response is carried out 0.5-2 hours.
In another preferred example, it in step (3-2), is mixed for the second time after reaction, including by obtained reaction
Object with alkali (such as alkaline aqueous solution, such as the aqueous solution of potassium hydroxide etc.) adjust PH to 7~8, then with acid (such as acid solution,
Such as dilute hydrochloric acid etc.) adjust precipitation precipitated products.The step for technical staff can also be carried out according to this field routine operation.
In step (3-2), the yield and purity of final products are helped to improve by control temperature etc., and help to simplify
The post-processing step of product.
In the method, compound (I) can also be recrystallized with acetone after step (3) or (3-2).
Compared with the synthetic method of previous literature report, method of the invention is mainly had the advantage that
Method of the invention operates extremely simple (first two only need grinding), at low cost, high income, reaction condition temperature
With and synthesis target product it is with high purity the advantages that, therefore be suitble to industrialized production.
Below with reference to specific implementation, the present invention is further explained.It should be understood that these embodiments be merely to illustrate the present invention and
It is not used in and limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition,
Or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.The present invention is implemented
Raw materials used or instrument in example, if not it illustrates, it is commercially available.
Embodiment 1:
(1), the preparation of compound (IV)
At room temperature, compound (II) (13.0g, 34.4mmol) and compound (III) (4.28g, 37.84mmol) are set
It in agate mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, according to
Secondary anhydrous sodium sulfate is dry by water and saturated common salt water washing, filters, be spin-dried for product compound (IV) (15.72g,
93%).
1HNMR (400MHz, CDC13):δ7.99-8.09(m,2H),7.01-7.09(m,2H),4.48-4.54(m,3H),
4.03-4.18(m,2H),3.63-3.70(m,6H),3.21-3.31(m,1H),2.63-2.68(m,2H),2.28-2.36(m,
5H),1.55-1.65(m,2H),1.23-1.29(m,3H)；C23H29N3O9(M+H)+Calcd:491.4911,found:
491.4928。
(2), the preparation of compound (VI)
At room temperature, compound (IV) (14.6g, 29.67mmol) and compound (V) (1.93g, 32.64mmol) are set
It in agate mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, according to
Secondary by saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous sodium sulfate is dry, filters, is spin-dried for obtaining product compound
(VI) (14.37g, 96%).
(3), the preparation of compound (I)
At room temperature, by compound (VI) (10.0g, 19.82mmol) and 2N sodium hydrate aqueous solution (20ml), in 40~
45 DEG C are stirred to react 2 hours, 0.3g silica gel (100~200 mesh) then are added, stirring is filtered after 15 minutes.Filtrate is placed in ice
It is down to 0~5 DEG C in water-bath, and 0 DEG C of 8N sulfuric acid solution (10ml) is added dropwise at this temperature, after being added dropwise and in the temperature
Lower stirring 1 hour.1N potassium hydroxide solution tune PH=7~8 are used at 0~5 DEG C, then dilute hydrochloric acid precipitated product is added dropwise, and are filtered, by institute
Solid obtain off-white powder with acetone recrystallization, be compound (I) (7.37g, 87%, purity: 99.87%).
Embodiment 2:
(1), the preparation of compound (IV)
At room temperature, compound (II) (13.0g, 34.4mmol) and compound (III) (3.88g, 34.4mmol) are set
It in agate mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, according to
Secondary anhydrous sodium sulfate is dry by water and saturated common salt water washing, filters, be spin-dried for product compound (IV) (15.05g,
89%).
1HNMR (400MHz, CDC13):δ7.99-8.09(m,2H),7.01-7.09(m,2H),4.48-4.54(m,3H),
4.03-4.18(m,2H),3.63-3.70(m,6H),3.21-3.31(m,1H),2.63-2.68(m,2H),2.28-2.36(m,
5H),1.55-1.65(m,2H),1.23-1.29(m,3H)；C23H29N3O9(M+H)+Calcd:491.4911,found:
491.4928。
(2), the preparation of compound (VI)
At room temperature, compound (IV) (14.6g, 29.67mmol) and compound (V) (1.93g, 32.64mmol) are set
It in agate mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, according to
Secondary by saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous sodium sulfate is dry, filters, is spin-dried for obtaining product compound
(VI) (14.22g, 95%).
(3), the preparation of compound (I)
At room temperature, by compound (VI) (10.0g, 19.82mmol) and 2N potassium hydroxide aqueous solution (20ml), in 40~
45 DEG C are stirred to react 2 hours, 0.3g silica gel (100~200 mesh) then are added, stirring is filtered after 15 minutes.Filtrate is placed in ice
It is down to 0~5 DEG C in water-bath, and 0 DEG C of 8N sulfuric acid solution (10ml) is added dropwise at this temperature, after being added dropwise and in the temperature
Lower stirring 1 hour.1N potassium hydroxide solution tune PH=7~8 are used at 0~5 DEG C, then dilute hydrochloric acid precipitated product is added dropwise, and are filtered, by institute
Solid obtain light gray solid with acetone recrystallization, be compound (I) (8.13g, 96%, purity: 99.68%).
Embodiment 3:
(1), the preparation of compound (IV)
At room temperature, compound (II) (13.0g, 34.4mmol) and compound (III) (4.28g, 37.84mmol) are set
It in agate mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, according to
Secondary anhydrous sodium sulfate is dry by water and saturated common salt water washing, filters, be spin-dried for product compound (IV) (15.89g,
94%).
1HNMR (400MHz, CDC13):δ7.99-8.09(m,2H),7.01-7.09(m,2H),4.48-4.54(m,3H),
4.03-4.18(m,2H),3.63-3.70(m,6H),3.21-3.31(m,1H),2.63-2.68(m,2H),2.28-2.36(m,
5H),1.55-1.65(m,2H),1.23-1.29(m,3H)；C23H29N3O9(M+H)+Calcd:491.4911,found:
491.4928。
(2), the preparation of compound (VI)
At room temperature, compound (IV) (14.6g, 29.67mmol) and compound (V) (1.75g, 29.67mmol) are set
It in agate mortar, mixes well, grinds 10min, sampling, TLC detection, reaction completion.Product is dissolved in ethyl acetate, according to
Secondary by saturated sodium carbonate solution, water and saturated common salt water washing, anhydrous sodium sulfate is dry, filters, is spin-dried for obtaining product compound
(VI) (13.62g, 91%).
(3), the preparation of compound (I)
At room temperature, by compound (VI) (10.0g, 19.82mmol) and 2N potassium hydroxide aqueous solution (15ml), in 40~
45 DEG C are stirred to react 2 hours, 0.3g silica gel (100~200 mesh) then are added, stirring is filtered after 15 minutes.Filtrate is placed in ice
It is down to 0~5 DEG C in water-bath, and 0 DEG C of 8N sulfuric acid solution (8.75ml) is added dropwise at this temperature, after being added dropwise and in the temperature
Degree lower stirring 1 hour.1N potassium hydroxide solution tune PH=7~8 are used at 0~5 DEG C, then dilute hydrochloric acid precipitated product is added dropwise, and are filtered, it will
Resulting solid obtains light gray solid with acetone recrystallization, be compound (I) (7.88g, 93%, purity: 99.83%).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of prepare N- { 4- { 2- (2- amino -4,7- dihydro -4- oxo -3H- pyrrolo- (2,3-d) pyrimidine -5- base) ethyl }
Benzoyl }-Pidolidone (I) method, which is characterized in that comprising steps of
(1) preparation of compound (IV):
Compound (II) and compound (III) are uniformly mixed, reacted under condition of no solvent by grinding, thus formed
It closes object (IV)；
(2) preparation of compound (VI)
Compound (IV) and compound (V) are uniformly mixed, reacted under condition of no solvent by grinding, to form chemical combination
Object (VI)；
(3) preparation of compound (I):
In atent solvent, in the presence of a catalyst, compound (VI) is subjected to cyclization and hydrolysis, so that it is bent to form training U.S.
It fills in (I).
2. the method according to claim 1, wherein
In step (1), the temperature of the reaction is 0~80 DEG C；And/or
In step (2), the temperature of the reaction is 0~80 DEG C；And/or
In step (3), the temperature of the reaction is -20~80 DEG C.
3. the method according to claim 1, wherein the inactive reagents are selected from the group in step (3): water,
Ethyl acetate, methanol, ethyl alcohol, isopropanol, methylene chloride, tetrahydrofuran, toluene, dimethylbenzene, or combinations thereof.
4. the method according to claim 1, wherein the step (3) comprising steps of
Compound (VI) in the presence of base catalyst, is carried out first set reaction, to form one in atent solvent by (3-1)
Reaction mixture；
(3-2) in presence of an acid catalyst, the reaction mixture that above-mentioned steps are obtained carries out the second secondary response, to form training
Beautiful Qu Sai (I).
5. according to the method described in claim 4, it is characterized in that, the base catalyst is selected from the group in step (3-1):
Potassium carbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium methoxide, ethyl alcohol
Sodium, or combinations thereof.
6. according to the method described in claim 4, it is characterized in that, the first set reaction is 30~55 in step (3-1)
It is carried out at DEG C.
7. according to the method described in claim 4, it is characterized in that, after first set reaction, also being wrapped in step (3-1)
It includes and filters reaction mixture with silica gel.
8. the method according to the description of claim 7 is characterized in that the silica gel is 100-200 purpose.
9. according to the method described in claim 4, it is characterized in that, the acid catalyst is selected from the group in step (3-2):
Sulfuric acid, hydrochloric acid, nitric acid, acetic acid, formic acid, or combinations thereof.
10. according to the method described in claim 4, it is characterized in that, in step (3-2), second secondary response -10~
It is carried out at 15 DEG C.
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| WO2005121137A1 (en) * | 2004-06-03 | 2005-12-22 | Brandeis University | Asymmetric michael and aldol addition using bifunctional cinchona-alkaloid-based catalysts |
| CN100379729C (en) * | 2006-04-06 | 2008-04-09 | 海南天源康泽医药科技有限公司 | Nitro compounds and their application in preparation of pemetrexed |
| CN101560206B (en) * | 2009-05-21 | 2011-06-22 | 苏州立新制药有限公司 | Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby |
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