CN110452180A - A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- - Google Patents
A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- Download PDFInfo
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- CN110452180A CN110452180A CN201910554931.9A CN201910554931A CN110452180A CN 110452180 A CN110452180 A CN 110452180A CN 201910554931 A CN201910554931 A CN 201910554931A CN 110452180 A CN110452180 A CN 110452180A
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- 238000000034 method Methods 0.000 title claims abstract description 33
- BNFCEIMRFKQNND-UHFFFAOYSA-N ethyl 5-amino-2-chloropyrimidine-4-carboxylate Chemical compound CCOC(=O)C1=NC(Cl)=NC=C1N BNFCEIMRFKQNND-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims description 13
- 238000003786 synthesis reaction Methods 0.000 title claims description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims abstract description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester Chemical compound 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims abstract description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960005010 orotic acid Drugs 0.000 claims abstract description 14
- OPGJGRWULGFTOS-UHFFFAOYSA-N 5-nitro-2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound OC(=O)C=1NC(=O)NC(=O)C=1[N+]([O-])=O OPGJGRWULGFTOS-UHFFFAOYSA-N 0.000 claims abstract description 13
- DAZDARINDDLSLS-UHFFFAOYSA-N ethyl 5-nitro-2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical compound CCOC(=O)C=1NC(=O)NC(=O)C=1[N+]([O-])=O DAZDARINDDLSLS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 11
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 235000019441 ethanol Nutrition 0.000 claims abstract description 7
- 239000000395 magnesium oxide Substances 0.000 claims abstract description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000007530 organic bases Chemical class 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 239000005457 ice water Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- 239000013067 intermediate product Substances 0.000 claims description 7
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 230000000630 rising effect Effects 0.000 claims description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000010813 municipal solid waste Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 239000005862 Whey Substances 0.000 claims 2
- 102000007544 Whey Proteins Human genes 0.000 claims 2
- 108010046377 Whey Proteins Proteins 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- DWRWSNAREGLUHZ-UHFFFAOYSA-N ethyl pyrimidine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=N1 DWRWSNAREGLUHZ-UHFFFAOYSA-N 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- NGCRXXLKJAAUQQ-UHFFFAOYSA-N undec-5-ene Chemical compound CCCCCC=CCCCC NGCRXXLKJAAUQQ-UHFFFAOYSA-N 0.000 claims 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WUTIIZNUZXLPGK-UHFFFAOYSA-N C(C)OC=O.N1=CC=CC=C1 Chemical compound C(C)OC=O.N1=CC=CC=C1 WUTIIZNUZXLPGK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- PYFMAAFCQDFHJX-UHFFFAOYSA-N ethyl pyrimidine-2-carboxylate Chemical compound CCOC(=O)C1=NC=CC=N1 PYFMAAFCQDFHJX-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- YFZBEXPQXKNNGJ-UHFFFAOYSA-N 5-amino-2-chloropyrimidine-4-carboxylic acid Chemical compound NC1=CN=C(Cl)N=C1C(O)=O YFZBEXPQXKNNGJ-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001546 nitrifying effect Effects 0.000 description 1
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of methods for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, first by fuming nitric aicd, the concentrated sulfuric acid and orotic acid, which react, is made nitroorotic acid, nitroorotic acid obtained and ethyl alcohol are mixed again, the concentrated sulfuric acid is added dropwise at room temperature, obtain nitroorotic acid ethyl ester, by nitroorotic acid ethyl ester, phosphorus oxychloride and organic base react 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, finally by 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, palladium carbon and magnesia mixing, it is added in tetrahydrofuran and carries out reacting obtained final product, the present invention is using commercially available orotic acid as raw material, by nitrification, esterification, chlorination and reduction reaction generate the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, present invention process is easy to operate, it is easy to operate, reaction is mild, it pollutes small, and it makes The pyrimidine yield and purity is high obtained, environmental pollution is small, and the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- produced by the present invention can be used for being mass produced.
Description
Technical field
The invention belongs to medicine intermediate field, specially a kind of side for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-
Method.
Background technique
Pyrimidine ring is drug, one of most common heterocycle in natural products, and pyrimidine heterocyclic compounds are such as synthesizing
The intermediate of drug has important application in field of medicaments, is widely used in anticancer drug, the research and development of anti-AIDS drug etc.
Clinically, therefore, the preparation process for developing and optimizing such compound, has great significance, but in the prior art, doctor
The synthetic route of medicine intermediate is long, and yield is low, and toxicity is big, more serious to the damage ratio of environment.
It is mainly used for synthesizing the medicine intermediate of the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, the chloro- 5- ammonia of 2- in the present invention
Base -6- pyrimidinecarboxylic acid ethyl ester is a kind of new medicine intermediate, and synthetic route is short, easy to operate, high income, and to environment without
Pollution.
Summary of the invention
The purpose of the present invention is to provide a kind of methods for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, on solving
State the problem of synthetic route proposed in background technique is long, and yield is low, and environmental pollution is serious.
To achieve the above object, the invention provides the following technical scheme: a kind of chloro- 5- amino -6- pyrimidinecarboxylic acid of synthesis 2-
The method of the method for ethyl ester, the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of synthesis 2- includes the following steps:
1) it is reacted after mixing fuming nitric aicd, the concentrated sulfuric acid and orotic acid by weight 1:1-5:2-5, reaction terminates
Afterwards, it is down to room temperature, is poured slowly into ice water, is stirred 1 hour, filtering washes filter cake to neutrality, digs out filter cake, dry to obtain nitro
Orotic acid；
2) nitroorotic acid and ethyl alcohol are mixed by weight 1:8-12, are added dropwise the concentrated sulfuric acid at room temperature, the concentrated sulfuric acid with
Nitroorotic acid weight ratio is 1:0.5-2, is then warming up to 70-80 DEG C of back flow reaction, is down to room temperature after reaction, is filtered,
Obtain nitroorotic acid ethyl ester；
3) by nitroorotic acid ethyl ester, phosphorus oxychloride and organic base by weight 1:5-10:3-7 mixing and at 25-100 DEG C
Lower progress chlorination reaction 2-5 hours removes extra phosphorus oxychloride for being concentrated under reduced pressure after mixture cooling, uses again after adding water quenching to go out
Organic solvent extraction, it is dry, intermediate product 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis- are obtained after concentration；
4) by the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 2,4- bis-, palladium carbon and magnesia are by weight 1:0.1-1:0.1-
0.4, it is added in the tetrahydrofuran of 10-25 times of volume and is reacted, filtered after reaction, filtrate is evaporated to obtain crude product, column chromatography
Obtain product.
Further, fuming nitric aicd and the concentrated sulfuric acid are mixed in step 1), it is external cooling with ice water, add in batches at 5-25 DEG C
Enter orotic acid, add and be stirred at room temperature 1 hour, is then heated to 30-60 DEG C of reaction 3-6 hours.
Further, the temperature rising reflux reaction time is 16-24 hours in step 2).
Further, water quenching is added to go out in step 3) to pour into 5 times of phosphorus oxychloride numbers into the mixture for removing phosphorus oxychloride
The trash ice of amount simultaneously stirs 2 hours.
Further, the reaction condition in step 4) is hydrogenation reaction 7-10 hours under normal pressure.
Further, organic base is triethylamine, diisopropyl ethyl amine, triisopropylamine, n,N-Dimethylaniline, N, N-
Diethylaniline, N, N- dimethyl pyrazole piperidinyl amine, pyridine, 1,8- diaza-bicyclic (5,4,0) endecatylene -7, two ring
The mixing of one or more of [4.3.0] -1,5- phenodiazine -5- hendecene.
The reaction equation of above-mentioned technical proposal can indicate are as follows:
Compared with prior art, the beneficial effects of the present invention are: the present invention is using commercially available orotic acid as raw material, by nitrifying,
Esterification, chlorination and reduction reaction generate the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, and present invention process is easy to operate, synthetic route
Short, easy to operate, reaction is mild, and pollution is small, and pyrimidine yield obtained and purity is high, and environmental pollution is small, and the present invention is made
The chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- can be used for being mass produced.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
Embodiment 1:
A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, the chloro- 5- amino -6- pyrimidine first of synthesis 2-
The method of acetoacetic ester includes the following steps:
1) 500 grams of fuming nitric aicds are added in 2 liters of there-necked flask, 720 grams of the concentrated sulfuric acid, outside ice is then slowly added dropwise
Water is cooling, and 200 grams of orotic acid is added portionwise at 20 DEG C, adds and is stirred at room temperature 1 hour, is then heated to 50 DEG C and reacts 4 hours,
After reaction, it is down to room temperature, is poured slowly into ice water, is stirred 1 hour, filtering, washing filter cake to neutrality digs out filter cake, dries
It is dry to obtain 234 grams of nitroorotic acid, 95% or more purity, yield 90.5%；
2) 1.5 liters of ethyl alcohol are added in 3 liters of reaction flask, 200 grams of nitroorotic acid is added, 200 milliliters dense is added dropwise
Sulfuric acid, then temperature rising reflux reacts 18 hours, cools down after reaction, filters, obtains 190 grams of nitroorotic acid ethyl ester, purity
95% or more, yield 83%；
3) by 150 grams of nitroorotic acid ethyl ester, 1100 grams and 600 grams of triethylamine mixing of phosphorus oxychloride and at 100 DEG C
It carries out chlorination reaction 4 hours, extra phosphorus oxychloride is removed by being concentrated under reduced pressure after mixture cooling, again with organic after adding water quenching to go out
Solvent extraction, it is dry, intermediate product 2 is obtained after concentration, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis- recrystallizes to obtain 153g
Sterling, 98% or more purity, yield 88%；
4) by 15 gram 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, 13 grams of palladium carbons, 2.5 grams of magnesia, addition 200 is in the least
It rises in THF, hydrogenation reaction 7 hours, filtering, palladium carbon recovery, filtrate is evaporated to obtain crude product, and column chromatographs to obtain the chloro- 5- amino -6- of 2-
5 grams of pyrimidinecarboxylic acid ethyl ester, 98% or more, yield 43%.
Embodiment 2:
A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, the chloro- 5- amino -6- pyrimidine first of synthesis 2-
The method of acetoacetic ester includes the following steps:
1) 600 grams of fuming nitric aicds are added in 2 liters of there-necked flask, 820 grams of the concentrated sulfuric acid, outside ice is then slowly added dropwise
Water is cooling, and 200 grams of orotic acid is added portionwise at 15 DEG C, adds and is stirred at room temperature 1 hour, is then heated to 48 DEG C and reacts 5 hours,
After reaction, it is down to room temperature, is poured slowly into ice water, is stirred 1 hour, filtering, washing filter cake to neutrality digs out filter cake, dries
It is dry to obtain 245 grams of nitroorotic acid, 95% or more purity, yield 95%；
2) 2 liters of ethyl alcohol are added in 3 liters of reaction flask, 200 grams of nitroorotic acid is added, 100 milliliters of dense sulphur is added dropwise
Acid, then temperature rising reflux reacts 14 hours, cools down after reaction, filters, obtains 205 grams of nitroorotic acid ethyl ester, purity 95%
More than, yield 90%；
3) by 150 grams of nitroorotic acid ethyl ester, 1500 grams and 600 grams of diisopropyl ethyl amine of phosphorus oxychloride, mixing is simultaneously
It is carried out chlorination reaction 5 hours at 100 DEG C, removes extra phosphorus oxychloride for being concentrated under reduced pressure after mixture cooling, water quenching is added to go out
It is extracted again with organic solvent afterwards, it is dry, intermediate product 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, weight are obtained after concentration
Crystallize to obtain 163g sterling, 98% or more purity, yield 94%；
4) by 15 gram 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, 10 grams of palladium carbons, 5 grams of magnesia are added 150 milliliters
In THF, hydrogenation reaction 7 hours, filtering, palladium carbon recovery, filtrate was evaporated to obtain crude product, column chromatograph the chloro- 5- amino -6- of 2- is phonetic
5.5 grams of pyridine Ethyl formate, 98% or more, yield 48%.
Embodiment 3:
A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, the chloro- 5- amino -6- pyrimidine first of synthesis 2-
The method of acetoacetic ester includes the following steps:
1) 200 grams of fuming nitric aicds are added in 2 liters of there-necked flask, 1000 grams of the concentrated sulfuric acid is then slowly added dropwise, outside is used
Ice water is cooling, and 200 grams of orotic acid is added portionwise at 10 DEG C, adds and is stirred at room temperature 1 hour, and it is small to be then heated to 45 DEG C of reactions 3
When, after reaction, it to be down to room temperature, be poured slowly into ice water, stirred 1 hour, filtering, washing filter cake to neutrality digs out filter cake,
Dry to obtain 169 grams of nitroorotic acid, 95% or more purity, yield 65.5%；
2) 1.6 liters of ethyl alcohol are added in 3 liters of reaction flask, 200 grams of nitroorotic acid is added, 120 milliliters dense is added dropwise
Sulfuric acid, then temperature rising reflux reacts 15 hours, cools down after reaction, filters, obtains 187 grams of nitroorotic acid ethyl ester, purity
95% or more, yield 82%；
3) by 150 grams of nitroorotic acid ethyl ester, 800 grams of phosphorus oxychloride and 200 grams of N, N- diethylaniline, mixing is simultaneously
It is carried out chlorination reaction 4.5 hours at 100 DEG C, removes extra phosphorus oxychloride for being concentrated under reduced pressure after mixture cooling, add water quenching
It is extracted again with organic solvent after going out, it is dry, intermediate product 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, weight are obtained after concentration
Crystallize to obtain 121g sterling, 98% or more purity, yield 69%；
4) by 15 gram 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, 3 grams of palladium carbons, 6 grams of magnesia are added 160 milliliters
In THF, hydrogenation reaction 7 hours, filtering, palladium carbon recovery, filtrate was evaporated to obtain crude product, column chromatograph the chloro- 5- amino -6- of 2- is phonetic
4 grams of pyridine Ethyl formate, 98% or more, yield 35%.
Embodiment 4:
A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, the chloro- 5- amino -6- pyrimidine first of synthesis 2-
The method of acetoacetic ester includes the following steps:
1) 250 grams of fuming nitric aicds are added in 2 liters of there-necked flask, 550 grams of the concentrated sulfuric acid, outside ice is then slowly added dropwise
Water is cooling, and 200 grams of orotic acid is added portionwise at 20 DEG C, adds and is stirred at room temperature 1 hour, is then heated to 40 DEG C and reacts 5 hours,
After reaction, it is down to room temperature, is poured slowly into ice water, is stirred 1 hour, filtering, washing filter cake to neutrality digs out filter cake, dries
It is dry to obtain 179 grams of nitroorotic acid, 95% or more purity, yield 69.4%；
2) 2.2 liters of ethyl alcohol are added in 3 liters of reaction flask, 200 grams of nitroorotic acid is added, 300 milliliters dense is added dropwise
Sulfuric acid, then temperature rising reflux reacts 19 hours, cools down after reaction, filters, obtains 202 grams of nitroorotic acid ethyl ester, purity
95% or more, yield 88%；
3) by 150 grams of nitroorotic acid ethyl ester, 1200 grams and 720 grams of n,N-Dimethylaniline of phosphorus oxychloride, mixing is simultaneously
It is carried out chlorination reaction 3.5 hours at 100 DEG C, removes extra phosphorus oxychloride for being concentrated under reduced pressure after mixture cooling, add water quenching
It is extracted again with organic solvent after going out, it is dry, intermediate product 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, weight are obtained after concentration
Crystallize to obtain 141g sterling, 98% or more purity, yield 80%；
4) by 15 gram 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis-, 6 grams of palladium carbons, 5.5 grams of magnesia, addition 165 is in the least
It rises in THF, hydrogenation reaction 7 hours, filtering, palladium carbon recovery, filtrate is evaporated to obtain crude product, and column chromatographs to obtain the chloro- 5- amino -6- of 2-
6.7 grams of pyrimidinecarboxylic acid ethyl ester, 98% or more, yield 59%.
When organic base is triethylamine, diisopropyl ethyl amine, triisopropylamine, N, accelerine, N, N- diethyl
Aniline, N, N- dimethyl pyrazole piperidinyl amine, pyridine, 1,8- diaza-bicyclic (5,4,0) endecatylene -7, two rings [4.3.0] -1 and
When the mixing of one of 5- phenodiazine -5- hendecene or multi-solvents, can equally it be prepared according to the method for the embodiment of the present invention 1
Obtain the chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis-, and the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of the 2- and above-described embodiment 2 to 4
The performance of the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of obtained 2- is identical.
From embodiment 1 to 4 as can be seen that the present invention using commercially available orotic acid as raw material, by nitrification, esterification, chlorination and also
Original reaction generate the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, under different reaction conditions, medicine intermediate obtained it is pure
Degree is all larger than 98%, and purity is higher, from the result that measures of experiment it is found that the chloro- 5- amino -6- pyrimidine of 2- obtained in embodiment 1
Yield obtained is more than or equal to 35% under the yield and embodiment 2-4 reaction condition of Ethyl formate, and embodiment 4 is obtained
The yield of the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- is up to 59%, and present invention process is easy to operate, synthetic route process
In intermediate product purity obtained it is higher, easy to operate, reaction is mild, and pyrimidine yield and purity is high is made, compared to existing
There are pyrimidine yield in technology and the relatively low problem of purity, the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- produced by the present invention can
For being mass produced.
It should be noted that, in this document, relational terms such as first and second and the like are used merely to a reality
Body or operation are distinguished with another entity or operation, are deposited without necessarily requiring or implying between these entities or operation
In any actual relationship or order or sequence.Moreover, the terms "include", "comprise" or its any other variant are intended to
Non-exclusive inclusion, so that the process, method, article or equipment including a series of elements is not only wanted including those
Element, but also including other elements that are not explicitly listed, or further include for this process, method, article or equipment
Intrinsic element.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (6)
1. a kind of method for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2-, it is characterised in that: the chloro- 5- amino-of synthesis 2-
The method of 6- pyrimidinecarboxylic acid ethyl ester includes the following steps:
1) it is reacted after mixing fuming nitric aicd, the concentrated sulfuric acid and orotic acid by weight 1:1-5:2-5, after reaction, drop
It to room temperature, is poured slowly into ice water, stirs 1 hour, filtering washes filter cake to neutrality, digs out filter cake, dry to obtain nitro whey
Acid；
2) nitroorotic acid and ethyl alcohol are mixed by weight 1:8-12, the concentrated sulfuric acid, the concentrated sulfuric acid and nitro is added dropwise at room temperature
Orotic acid weight ratio is 1:0.5-2, is then warming up to 70-80 DEG C of back flow reaction, is down to room temperature after reaction, filters, obtains nitre
Base whey acetoacetic ester；
3) by nitroorotic acid ethyl ester, phosphorus oxychloride and organic base by weight 1:5-10:3-7 mix and at 25-100 DEG C into
Row chlorination reaction 2-5 hours, extra phosphorus oxychloride is removed by being concentrated under reduced pressure after mixture cooling, again with organic after adding water quenching to go out
Solvent extraction, it is dry, intermediate product 2, the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 4- bis- are obtained after concentration；
4) by the chloro- 5- nitro -6- pyrimidinecarboxylic acid ethyl ester of 2,4- bis-, palladium carbon and magnesia add by weight 1:0.1-1:0.1-0.4
Enter and reacted in the tetrahydrofuran of 10-25 times of volume, filtered after reaction, filtrate is evaporated to obtain crude product, and column chromatographs to obtain product.
2. a kind of method for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- according to claim 1, it is characterised in that:
Fuming nitric aicd and the concentrated sulfuric acid are mixed in the step 1), it is external cooling with ice water, orotic acid is added portionwise at 5-25 DEG C, adds
It is stirred at room temperature 1 hour, is then heated to 30-60 DEG C of reaction 3-6 hours.
3. a kind of method for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- according to claim 1, it is characterised in that:
The temperature rising reflux reaction time is 16-24 hours in the step 2.
4. a kind of method for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- according to claim 1, it is characterised in that:
In the step 3) plus water quenching is gone out to pour into trash ice and the stirring of 5 times of phosphorus oxychloride quantity into the mixture for removing phosphorus oxychloride
2 hours.
5. a kind of method for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- according to claim 1, it is characterised in that:
Reaction condition in the step 4) is hydrogenation reaction 7-10 hours under normal pressure.
6. a kind of method for synthesizing the chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- according to claim 1, it is characterised in that:
The organic base be triethylamine, diisopropyl ethyl amine, triisopropylamine, n,N-Dimethylaniline, N, N- diethylaniline, N,
N- dimethyl pyrazole piperidinyl amine, pyridine, 1,8- diaza-bicyclic (5,4,0) endecatylene -7, two ring [4.3.0] -1,5- phenodiazine -
The mixing of one or more of 5- hendecene.
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