CN1915976B - Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate - Google Patents
Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 12
- 239000000460 chlorine Substances 0.000 title description 2
- 229910052801 chlorine Inorganic materials 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 24
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 16
- 229960000583 acetic acid Drugs 0.000 claims description 13
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- ZPLQIPFOCGIIHV-UHFFFAOYSA-N Gimeracil Chemical compound OC1=CC(=O)C(Cl)=CN1 ZPLQIPFOCGIIHV-UHFFFAOYSA-N 0.000 abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 8
- 238000011084 recovery Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- -1 4-nitropyridine N-oxide compound Chemical class 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- ZEZJPIDPVXJEME-UHFFFAOYSA-N 2,4-Dihydroxypyridine Chemical compound OC=1C=CNC(=O)C=1 ZEZJPIDPVXJEME-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MYMNBFURSYZQBR-UHFFFAOYSA-N 5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CCCC(O)=O MYMNBFURSYZQBR-UHFFFAOYSA-N 0.000 description 1
- 102100036360 Cadherin-3 Human genes 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 102100022334 Dihydropyrimidine dehydrogenase [NADP(+)] Human genes 0.000 description 1
- 108010066455 Dihydrouracil Dehydrogenase (NADP) Proteins 0.000 description 1
- 101000714553 Homo sapiens Cadherin-3 Proteins 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229950009822 gimeracil Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
This invention relates to a method for preparing 5-chloro-4-hydroxy-2(1H)-pyridone. This invention also discloses a new intermediate for the compound and its preparation method.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to the preparation method of 5-chlorine 4-hydroxyl-2 (1H)-pyridone, the invention also discloses the new intermediate of institute's synthetic in the preparation.
Background technology
5-chloro-4-hydroxyl-2 (1H)-pyridone (CDHP, Gimeracil, I) be the biological regulator of 5 FU 5 fluorouracil (5-FU), the activity that can effectively suppress dihydropyrimidine dehydrogenase, worldwide be widely used in clinical antitumor, and obtained curative effect preferably, had characteristics such as safe, potent and long-acting.
The synthetic method of 5-chloro-4-hydroxyl-2 (1H)-pyridone mainly contains 5 kinds at present:
Method one (Rec Trav Chim.1954,73:704; Ibid.1953,72:853; J Heterocycl Chem.1975,12:389):
With 4-nitropyridine N-oxide compound is raw material, gets through the reaction of 5 steps, and total recovery 12% wherein need be used tube sealing reaction.
Method two (Rec Trav Chim.1954,73:704; Ibid.1953,72:853; Ber.1898,31:1682):
With 3-oxo-1, the 5-ethyl glutarate is a raw material, gets through the reaction of 6 steps, and total recovery 26% wherein need be used tube sealing reaction.
Method three (Rec Trav Chim.1954,73:704; Ibid.1953,72:853; J Heterocycl Chem.1977,14:1295):
With 1-methoxyl group-monovinylacetylene is raw material, gets through the reaction of 6 steps, and total recovery 25% wherein need be used tube sealing reaction.
Method four (Rec Trav Chim.1953,72:285):
With 4-nitropyridine-N-oxide compound is raw material, gets total recovery 13% through the reaction of 7 steps.
Method five (Hetercycl.1993,36:145):
With the propane dinitrile is raw material, gets crude product total recovery 74% through the reaction of 4 steps.Reaction formula is as follows:
Among the above-mentioned existing preparation method, the total recovery of method one to four is lower, and reaction conditions is harsh.The reaction step of method five is poly-shorter, yield is higher, but we are when the reaction of repetition methods five, discovery is by propane dinitrile and 1,1,1-trimethoxy-ethane and N, dinethylformamide dimethylacetal prepared in reaction 1,1-dicyano-2-methoxyl group-4-(N, the N-dimethylamino)-1,3-divinyl (IV), and by compound IV cyclization in water-containing acetic acid become the yield of 3-cyano group-4-methoxyl group-2 (1H)-pyridone (II) and document (Hetercycl.1993,36:145) suitable, but press document (Hetercycl.1993 by Compound I I and sulfuryl chloride, after condition 36:145) is reacted, can not get pure 5-chloro-3-cyano group-4-methoxyl group-2 (1H)-pyridone (V) through the routine processing, yield is lower after column chromatography for separation.After through groping, find that reaction need carry out at a lower temperature, but the reaction times then need to prolong (greater than 24 hours) greatly, just can obtain the compound V of higher yields.In addition, we also find, lucifuge helps reaction carries out, even react under common fluorescent lamp, speed of response reduces greatly, and the sulfuryl chloride consumption obviously increases, and analyze reason and may be due to sulfuryl chloride decomposes under the illumination.Compound V presses document (Hetercycl.1993,36:145) method can not get required product I with 40% sulphuric acid hydrolysis, but by product 5-chloro-3-cyano group-4-hydroxyl-2 (1H)-pyridone (VI), use 47% Hydrogen bromide hydrolysis instead and can obtain product, but color is darker, and fusing point is still on the low side behind recrystallization.
Summary of the invention
It is simple to the objective of the invention is to seek a kind of reaction conditions, constant product quality, the preparation method of 5-chloro-4-hydroxyl-2 (1H)-pyridone (I) that yield is higher.
We find as slowly join Compound I I in the chloride solution under study for action, finish again and under certain temperature, reacted 10 minutes to 2 hours, get final product purely 2,5-two chloro-3-cyano group-4-methoxypyridines (III), III is through aqueous sulfuric acid or hydrobromic acid aqueous solution hydrolysis, in with cyan-hydrolysis decarboxylation and methoxyl group demethylation, 2 chlorine atoms can be hydrolyzed into hydroxyl, and then isomery turns to object 5-chloro-4-hydroxyl-2 (1H)-pyridone (I).Reaction formula is as follows:
When preparing compound III by Compound I I, Compound I I can the solid form join in the solution of SULPHURYL CHLORIDE, also can will be added dropwise in the solution of SULPHURYL CHLORIDE after Compound I I and an amount of solvent.
When preparing compound III by Compound I I, the molar ratio of Compound I I and SULPHURYL CHLORIDE can be 1: 1.1～5, is preferably 1: 2.5, is more preferably 1: 2, and best is 1: 1.4.
Used reaction solvent can be a Glacial acetic acid when preparing compound III by Compound I I, water-containing acetic acid, DMF, N,N-dimethylacetamide, the DMSO and the mixture of two kinds or multiple solvent wherein.Best is Glacial acetic acid.
The temperature of reaction of Compound I I and SULPHURYL CHLORIDE can be 5～75 ℃, is preferably 25～55 ℃, and best is 45～50 ℃.
Used sulfuric acid concentration can be 45%～90% (per-cent of solvent for use of the present invention all is weight percentage) during the compound III hydrolysis, is more preferably 60%～80%.
Used Hydrogen bromide concentration is 40%～47% during the compound III hydrolysis.
The hydrolysis temperature of compound III can be 90～140 ℃, is more preferably 100～125 ℃.
5-chloro-4-hydroxyl-2 (1H)-pyridone (I) with the method for preparing gained, test by analysis, content is greater than 99%, related substance is less than 0.5%, this shows, prepare Compound I, not only have good product quality with this law, reaction times is short, yield is high (the highly finished product total recovery is greater than＞70%), low cost and other advantages, and easier realization suitability for industrialized production.
The present invention has also obtained new intermediate, i.e. a compound III:
Formula II compound is joined in the chloride solution promptly.
Embodiment
Embodiment 1
2,5-two chloro-3-cyano group-4-methoxypyridines (III)
SULPHURYL CHLORIDE 13.0ml (0.16mol) and Glacial acetic acid 280ml are mixed, and lucifuge is under the stirring at room, drip the suspension that 3-cyano group-4-methoxyl group-2 (1H)-pyridone 20g (0.133mol) and 100ml Glacial acetic acid are formed, drip complete, in 50 ℃ of stirring reactions 15 minutes, add SULPHURYL CHLORIDE 2.0ml (0.025mol), reacted 15 minutes, the reclaim under reduced pressure solvent adds methyl alcohol and each 12ml of isopropyl ether in the residue, cold back suction filtration, get off-white color crystal III24.2g, yield 89.4%, m.p.166-168 ℃.
1H-NMR(DMSO-d
6，500MHz)δ：4.29(s，3H，OCH
3)，7.89(s，1H，ArH)；MS(ESI(+)70V，m/z)：203.1(M+H)
+。
Embodiment 2
2,5-two chloro-3-cyano group-4-methoxypyridines (III)
SULPHURYL CHLORIDE 9.6ml (0.12mol) and Glacial acetic acid 150ml are mixed, under the stirring at room, drip the suspension of 3-cyano group-4-methoxyl group-2 (1H)-pyridone 10g (0.067mol) and 50ml Glacial acetic acid, drip complete, in 50 ℃ of stirring reactions 30 minutes, the reclaim under reduced pressure solvent, add methyl alcohol and each 7.5ml of isopropyl ether in the residue, cold back suction filtration gets off-white color crystal III11.3g, yield 83.5%, m.p.166-168 ℃.
Embodiment 3
2,5-two chloro-3-cyano group-4-methoxypyridines (III)
SULPHURYL CHLORIDE 7.0ml (0.087mol) and Glacial acetic acid 100ml are mixed, and lucifuge is under the stirring at room, drip the suspension of 3-cyano group-4-methoxyl group-2 (1H)-pyridone 10g (0.067mol) and 100ml DMF, drip complete, in 55 ℃ of stirring reactions 20 minutes, add SULPHURYL CHLORIDE 1.0ml (0.012mol), reacted 30 minutes, the reclaim under reduced pressure solvent adds methyl alcohol and each 7.5ml of isopropyl ether in the residue, cold back suction filtration, get off-white color crystal III10.8g, yield 79.8%, m.p.165-167 ℃.
Embodiment 4
2,5-two chloro-3-cyano group-4-methoxypyridines (III)
SULPHURYL CHLORIDE 8.6ml (0.107mol) and Glacial acetic acid 180ml are mixed, lucifuge under the stirring at room, repeatedly adds 3-cyano group-4-methoxyl group-2 (the 1H)-pyridone l0g (0.067mol) of porphyrize on a small quantity, finish, in 50 ℃ of stirring reactions 45 minutes, reclaim under reduced pressure solvent, add methyl alcohol and each 7.5ml of isopropyl ether in the residue, cold back suction filtration, get off-white color crystal III11.6g, yield 85.7%, m.p.166-168 ℃.
Embodiment 5
5-chloro-4-hydroxyl-2 (1H)-pyridone (I)
With 2,5-two chloro-3-cyano group-4-methoxypyridine (III) 20g (0.099mol), 75% sulphuric acid soln l00ml, temperature stirred 3 hours down outside 140 ℃, and reaction is finished, and neutralizes with 20% sodium hydroxide, transfer pH 4.0-4.5 with 5% hydrochloric acid again, separate out solid, filter, the washing, dry off-white color solid 12.8g, crude product yield 89.3%, with 65% ethanol refining white powdery crystallization I11.5g, yield 80.2%, m.p.276-278 ℃ (decomp.), document m.p.277-279 ℃ (decomp.).
1H-NMR(DMSO-d
6，500MHz)δ：5.72(s，1H，ArH)，7.52(s，1H，ArH)，11.37(brs，2H，OH)；MS(ESI(+)70V，m/z)：146.2(M+H)
+。
Claims (6)
1. the preparation method of a formula I compound comprises following preparation process:
Used reaction solvent is selected from Glacial acetic acid, water-containing acetic acid, N when preparing compound III by Compound I I, dinethylformamide, N,N-dimethylacetamide or methyl-sulphoxide, and the mixture of above-mentioned two kinds or multiple solvent; During preparation Compound I I is slowly joined in the chloride solution, the temperature of reaction of Compound I I and SULPHURYL CHLORIDE is 25～65 ℃.
2. the preparation method of claim 1, when preparing compound III by Compound I I, the molar ratio of Compound I I and SULPHURYL CHLORIDE is 1: 1.1～5.
3. the preparation method of claim 2, when preparing compound III by Compound I I, the molar ratio of Compound I I and SULPHURYL CHLORIDE is 1: 1.4.
4. the preparation method of claim 1, used reaction solvent is a Glacial acetic acid when preparing compound III by Compound I I.
5. the described preparation method of claim 1, during the compound III hydrolysis used sulfuric acid concentration be 60%～80% or used Hydrogen bromide concentration be 40%～47%, hydrolysis temperature is 90～140 ℃.
6. the midbody compound of a structural formula II I:
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| CN200610086191A CN1915976B (en) | 2006-09-08 | 2006-09-08 | Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate |
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| CN200610086191A CN1915976B (en) | 2006-09-08 | 2006-09-08 | Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921227B (en) * | 2007-04-03 | 2012-09-05 | 南京工业大学 | 5-chloro-4-hydroxyl-2(1H)-pyridone crystal form, preparation method and application thereof |
| CN103159673B (en) * | 2011-12-12 | 2015-02-04 | 山东新时代药业有限公司 | Refining method for preparing gimeracil |
| CN102977013B (en) * | 2012-11-07 | 2014-08-27 | 河南师范大学 | Simple and effective method for high-selectivity removal of alpha-monomethyl of 2,6-dimethyl-4-pyridone derivative |
| CN102993088A (en) * | 2012-12-31 | 2013-03-27 | 东华大学 | 4-hydroxy-2-pyridone preparation method |
| CN103664772B (en) * | 2013-11-29 | 2016-08-24 | 齐鲁工业大学 | The synthetic method of 5-chloro-3-cyano group-4-methoxyl group-2 (1 H) pyridone |
| CN104592102B (en) * | 2015-01-16 | 2017-03-08 | 南京正大天晴制药有限公司 | A kind of composition of gimeracil and preparation method thereof |
| CN111303047B (en) * | 2020-03-27 | 2023-04-25 | 上海阿拉丁生化科技股份有限公司 | Synthesis method of 2-amino-4, 6-lutidine |
| CN113861106A (en) * | 2021-10-26 | 2021-12-31 | 山东安舜制药有限公司 | Production process of high-purity medicinal gimeracil |
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| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: Liuhe District of Nanjing City, Jiangsu province 211511 Tan Lu No. 8 Patentee after: Nanjing East Sunscreen Pharmaceutical Co.,Ltd. Address before: The seven floor No. 187 vegetable branch building 210042 Nanjing City, Jiangsu province Longpan Road Patentee before: Nanjing East Sunscreen Pharmaceutical Co.,Ltd. |
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| CP02 | Change in the address of a patent holder |
Address after: 211511 Nanjing Taiwanese Business Industrial Park, Nanjing, Jiangsu Province (Liuhegua Port) Patentee after: Nanjing East Sunscreen Pharmaceutical Co.,Ltd. Address before: 211511 No. 8 Tanzi Road, Liuhe District, Nanjing City, Jiangsu Province Patentee before: Nanjing East Sunscreen Pharmaceutical Co.,Ltd. |
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| CP02 | Change in the address of a patent holder |