CN102199154B - Novel synthesis method for pyrrole derivatives - Google Patents
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- 150000003233 pyrroles Chemical class 0.000 title abstract description 5
- 238000001308 synthesis method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 230000006837 decompression Effects 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- -1 sec.-propyl Chemical group 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 6
- 238000002360 preparation method Methods 0.000 abstract description 4
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 abstract 2
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- WENZNTBBHOBISN-UHFFFAOYSA-N pyrrole-1,2-dicarboxylic acid Chemical compound OC(=O)C1=CC=CN1C(O)=O WENZNTBBHOBISN-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000021419 vinegar Nutrition 0.000 description 4
- 239000000052 vinegar Substances 0.000 description 4
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
Abstract
The invention relates to a novel method for high-efficiency preparation of pyrrole 1,2-dicarboxylic acid and derivatives thereof. Pyrrole derivatives are synthesized from inexpensive and easily available 2-pyrrole carboxylic acid ester compound used as a raw material through bromination, decarboxylation and other unit reactions easy and simple to operate.
Description
Technical field
The present invention relates to the organic synthesis such as medicine, agricultural chemicals and dyestuff field, be mainly the novel method of the adjacent disubstituted derivatives of a kind of efficient preparation pyrroles.
Background technology
Formula (I)
Suc as formula the important intermediate that is a class in the organic synthesis such as medicine, agricultural chemicals and dyestuff field of the chemical structure shown in (I), for example at Chemical and Pharmaceutical Bulletin, 1997, vol.45, #10, p.1642-1652 mention in, formula (I) compound and the single fluorobenzene that are methyl with R react as NK
1The important method that the receptor antagonist candidate compound is synthetic.
Present published similar compound comprises following compound at least:
Due to the special property of electron rich pyrrole ring, make adjacent disubstituted pyrroles compounds especially 2,3-disubstituted pyrroles compound synthetic more difficult, its synthetic method rarely has report at present.
Summary of the invention:
Technical problem to be solved by this invention is to provide the method for a kind of rational synthesis type (I).
Wherein, the R base is selected from methyl, ethyl, propyl group, sec.-propyl, phenyl, halogenophenyl, haloalkyl phenyl, benzyl.Method of the present invention comprises:
A, starting raw material S1 is carried out the dibrominated after saponification at 2,3, decarboxylation forms intermediate S4;
B, S4 is carried out R base replace on N, then by with the metal reagent permutoid reaction, pass into CO
2, acidifying obtains S6;
C, the dehydration of adjacent dicarboxylic acid form formula (I) compound.
In above-mentioned reactions steps A, dibrominated can also replace in two iodate, and subsequent step is consistent.
The reaction conditions of above-mentioned reactions steps A is, S1 is dissolved in for example tetracol phenixin of organic solvent under the existence of catalytic amount iodine, then at room temperature slowly drips the carbon tetrachloride solution of bromine, at room temperature stirs after dripping off, and decompression steams solvent, obtains S2; S2 is added 20% NaOH solution, in 60～90 ℃ of reaction 2～6h, then be acidified to pH 2-3 with 6N HCl, treat that a large amount of white solids separate out, filtration final vacuum drying obtains S3; S3 is added appropriate monoethanolamine, in 100 ℃ of heated and stirred 1-3h, be cooled to room temperature after end, add entry, with organic solvent extracted with diethyl ether for example; The extraction liquid washing is dry, and concentrating under reduced pressure is directly used in next step reaction;
The reaction conditions of above-mentioned reactions steps B is that S4 solution in 0 ℃, is slowly dropped in the DMF solution of sodium hydride, after stirring 15min, slowly drip BrR, wherein the definition of R base is the same, then rises to room temperature reaction 2-4h, after end, reaction solution is slowly poured in frozen water, and with organic solvent extracted with diethyl ether for example, the organic phase washing is dry, concentrating under reduced pressure uses column chromatography purifying and obtains light yellow liquid S5; S5 is dissolved in organic solvent for example in THF, is cooled to-78 ℃, slowly drip n-BuLi or MAGNESIUM METAL grignard reagent, stir 30min under-78 ℃, pass into CO
2Then gas reaction 1-2.5h slowly rises to room temperature, continues stirring reaction 1-2h.After reaction finishes, reaction solution is slowly poured in frozen water, being acidified to pH with 2N dilute hydrochloric acid is 2 left and right, and with organic solvent ethyl acetate extraction for example, drying after concentrating under reduced pressure, is carried out column chromatography and got the white solid compound s 6;
The reaction conditions of above-mentioned reactions steps C is that with compound s 6 and the dried reflux 3-4h of vinegar, decompression steams vinegar and does, and then can get white solid compound formula (I) by purification by silica gel column chromatography.
The present invention also provides a kind of new intermediate S7, and its structural formula is
Beneficial effect of the present invention is:
One, provide a kind of feasible preparation 2, the synthetic route of 3-pyrroles's acid anhydrides, and can be used for further reaction formation 2,3-disubstituted pyrroles compound;
Two, the yield of each step reaction is higher, more than 74%;
Three, provide a kind of alternative new intermediate S7.
Embodiment:
Content of the present invention is further elaborated by following embodiment, but does not limit the scope of the invention.Embodiment: preparation 1-ethyl-3-(4-fluorobenzoyl)-1H-pyrroles-2-carboxylic acid (1)
With S1 (2.0g, 14.4mmol) and catalytic amount iodine (3mg) be placed in the single port flask of 100ml, adding the 40ml tetracol phenixin dissolves it, then at room temperature slowly drip bromine (4.6g, 28.8mmol) tetracol phenixin (20ml) solution, at room temperature stir 2h after dripping off, decompression steams the solid crude product of solvent, then purification by silica gel column chromatography (PE/EtOAc=30/1-20/1) obtains 4.05g compound S 2, productive rate 95.0%.
With S2 (2.0g, 6.7mmol) be placed in the single port flask of 100ml, add 20% NaOH solution (20ml), in 85 ℃ of reaction 4h, then be acidified to pH 2-3 with 6N HCl, a large amount of white solids are separated out, and filter final vacuum dry, get 1.78g white solid compound S 3, productive rate 98.3%.
S3 (1g, 3.7mmol) is placed in the single port flask of 50ml, adds the 10ml monoethanolamine, in 100 ℃ of heated and stirred 2h, be cooled to room temperature after end, add 40ml water, with ether (30ml*3) extraction; Ether extraction liquid is used respectively 2N dilute hydrochloric acid, saturated common salt water washing once, then uses anhydrous sodium sulfate drying, and the S4 solution that is evaporated to 20ml is directly used in next step reaction.
With S4 solution in 0 ℃, slowly drop to sodium hydride (297.5mg, 7.4mmol) DMF (10ml) solution in, after stirring 15min, slowly drip monobromethane (806.4g, 7.4mmol), then rise to room temperature reaction 4h, after end, slowly pour into reaction solution in frozen water, with extracted with diethyl ether (30ml*3), then organic phase with the saturated common salt water washing once uses anhydrous sodium sulfate drying, concentrating under reduced pressure, with silicagel column separation and purification (eluent: PE/EtOAc=40/1-30/1) obtain 696.1mg light yellow liquid S5, productive rate 74.0%.
S5 (696.1mg, 2.75mmol) is dissolved in THF (15ml), and solution is placed in the low-temp reaction instrument, is cooled to-78 ℃, slowly drips n-BuLi (1.6M, 3.6ml), stirs 30min under-78 ℃, passes into CO
2Then gas reaction 1.5h slowly rises to room temperature, continues stirring reaction 1h.After reaction finishes, slowly pour into reaction solution in frozen water, being acidified to pH with 2N dilute hydrochloric acid is 2 left and right, use ethyl acetate extraction, anhydrous sodium sulfate drying, after concentrating under reduced pressure, carry out silica gel column chromatography (eluent: PE/EtOAc=5/1-1/1) get 320.2mg white solid compound s 6, productive rate 75.0%.
With compound s 6 (100mg, 0.55mmol) and the dried 50ml single port flask that is placed in of 10ml vinegar, reflux 3-4h, decompression steams vinegar and does, then (eluent: PE/EtOAc=10/1-5/1) purifying can get 85.6mg white solid compound S 7, productive rate 95.0% by silica gel column chromatography.
H-NMR(300MHz，DMSO-d
6)：7.92(d，1H)，6.25(d，1H)，4.36(q，2H)，1.36(t，3H)
Compound S 7 (50mg, 0.30mmol) is dissolved in the 3ml fluorobenzene, then slowly drops to anhydrous AlCl
3(60mg, 0.45mmol) and the mixture of fluorobenzene (5ml) in, reflux 3-4h, after end, reaction solution being poured in frozen water, is 2 left and right with the salt acid for adjusting pH of 6N, uses ethyl acetate extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure is with silicagel column separation and purification (eluent: PE/EtOAc=10/1-5/1) obtain 62.5mg compound 1, productive rate 79.1%.
The product that makes is tested, and result is as follows:
1H-NMR(300M，DMSO-d
6)δ12.72(s，1H)，7.80(m，2H)，7.31(m，2H)，7.22(d，1H)，6.28(d，1H)，4.36(q，2H)，1.36(t，3H)。
Claims (8)
1. the method for a synthesis type (I),
Wherein, the R base is selected from methyl, ethyl, propyl group, sec.-propyl, benzyl, it is characterized in that described method comprises:
A, starting raw material S1 is carried out the dibrominated after saponification at 4,5, decarboxylation forms intermediate S4;
B, S4 is carried out R base replace on N, then by with the metal reagent permutoid reaction, pass into CO
2, acidifying obtains S6;
The adjacent dicarboxylic acid dehydration of C, S6 forms formula (I) compound.
2. method according to claim 1, is characterized in that in reactions steps A, dibrominated can replace in two iodate.
3. method according to claim 1, is characterized in that in reactions steps A, S1 being dissolved in tetracol phenixin under the existence of catalytic amount iodine, then at room temperature slowly drip the carbon tetrachloride solution of bromine, at room temperature stir after dripping off, decompression steams solvent, obtains S2
4. method according to claim 3 is characterized in that S2 is added 20% NaOH solution, in 60 ~ 90 ℃ of reaction 2 ~ 6h, then is acidified to pH2-3 with 6N HCl, treats that a large amount of white solids separate out, and filtration final vacuum drying obtains S3
5. method according to claim 4, is characterized in that S3 is added monoethanolamine, in 100 ℃ of heated and stirred 1-3h, is cooled to room temperature after end, adds entry, uses extracted with diethyl ether; The extraction liquid washing is dry, and the S4 solution of concentrating under reduced pressure is directly used in next step reaction.
6. method according to claim 1, is characterized in that in reactions steps B, with S4 solution in 0 ℃, slowly drop in the DMF solution of sodium hydride, after stirring 15min, slowly drip BrR, wherein the definition of R base is with claim 1, then rise to room temperature reaction 2-4h, after end, slowly pour into reaction solution in frozen water, use extracted with diethyl ether, the organic phase washing is dry, and concentrating under reduced pressure uses column chromatography purifying and obtains light yellow liquid S5
7. method according to claim 6, is characterized in that S5 is dissolved in THF, is cooled to-78 ℃, slowly drips n-BuLi or MAGNESIUM METAL grignard reagent, stirs 30min under-78 ℃, passes into CO
2Then gas reaction 1-2.5h slowly rises to room temperature, continues stirring reaction 1-2h; Reaction is slowly poured reaction solution in frozen water after finishing, and being acidified to pH with 2N dilute hydrochloric acid is 2 left and right, uses ethyl acetate extraction, and drying after concentrating under reduced pressure, is carried out silica gel column chromatography and got the white solid compound s 6.
8. method according to claim 1, is characterized in that in reactions steps C, and with compound s 6 and aceticanhydride reflux 3-4h, decompression steams aceticanhydride, then can get white solid compound formula (I) by column chromatography purification.
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| CN 201110024849 CN102199154B (en) | 2011-01-24 | 2011-01-24 | Novel synthesis method for pyrrole derivatives |
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| CN 201110024849 CN102199154B (en) | 2011-01-24 | 2011-01-24 | Novel synthesis method for pyrrole derivatives |
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| CN102199154B true CN102199154B (en) | 2013-06-19 |
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| CN103232461A (en) * | 2013-05-21 | 2013-08-07 | 苏州科捷生物医药有限公司 | Synthesis method of 4-chloroquine anhydride |
| CN104201009B (en) * | 2014-09-03 | 2017-03-01 | 齐鲁工业大学 | A kind of preparation method of the polymer with nitrogen for electrode material for super capacitor |
| CN109694343B (en) * | 2018-12-19 | 2020-07-28 | 帕潘纳(北京)科技有限公司 | Decarboxylation method of heterocyclic carboxylic acid compounds |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4231785A (en) * | 1979-05-21 | 1980-11-04 | Shell Oil Company | Herbicide antidotes |
-
2011
- 2011-01-24 CN CN 201110024849 patent/CN102199154B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4231785A (en) * | 1979-05-21 | 1980-11-04 | Shell Oil Company | Herbicide antidotes |
Non-Patent Citations (5)
| Title |
|---|
| Gribble, Gordon W..Product subclass 14: aryllithium and hetaryllithium compounds.《Science of Synthesis》.2006,(第8a期),357-426. |
| Potent NK1 Receptor Antagonists: Synthesis and Antagonistic Activity of Various Heterocycles with an N-[3,5-Bis(trifluoromethyl)benzyl]-N-methylcarbamoyl Substituent;Yoshinori IKEURA, et al.;《Chem. Pharm. Bull.》;19971231;第45卷(第10期);1642-1652 * |
| Product subclass 14: aryllithium and hetaryllithium compounds;Gribble, Gordon W.;《Science of Synthesis》;20061231(第8a期);357-426 * |
| Yanbing Liu,et al..Generation and reactions of 2,3-dilithio-N-methylindole. Synthesis of 2,3-disubstituted indoles.《Tetrahedron Letters》.Elsevier Science Ltd.,2001,第42卷2949-2951. * |
| YoshinoriIKEURA et al..Potent NK1 Receptor Antagonists: Synthesis and Antagonistic Activity of Various Heterocycles with an N-[3 |
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Effective date of registration: 20150331 Address after: 211800, No. 8, prosperous road, Pukou Economic Development Zone, Jiangsu, Nanjing Patentee after: Nanjing Simcere Dongyuan Pharmaceutical Co., Ltd. Patentee after: Jiangsu Simcere Pharmaceutical Co., Ltd. Address before: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Patentee before: Jiangsu Simcere Pharmaceutical Research Company Limited |
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| CP03 | Change of name, title or address |
Address after: No.99, Huakang Road, Jiangbei new district, Nanjing, Jiangsu Province, 210032 Patentee after: SIMCERE PHARMACEUTICAL Group Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 211800, No. 8, prosperous road, Pukou Economic Development Zone, Jiangsu, Nanjing Patentee before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
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| CP03 | Change of name, title or address |