CN102399162A - Method for synthesizing chloramphenicol from 4-chloro-benzaldehyde - Google Patents
Method for synthesizing chloramphenicol from 4-chloro-benzaldehyde Download PDFInfo
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Abstract
The invention relates to a method for synthesizing a broad spectrum antibiotic, namely, chloramphenicol. The method comprises the following steps of: synthesizing (1R,2R)-2-nitro-1-(4-chlorophenyl)-1,3-propanediol by using 4-chlorobenzaldehyde and 2-nitroethylalcohol as raw materials in the presence of a chiral catalyst, and performing catalytic hydrogenation to obtain (1R,2R)-2-amino-1-(4-chlorophenyl)-1,3-propanediol; and performing dichloro acetylization and nitro substitution on the intermediate to obtain the chloramphenicol. By the method, the common chiral resolution and aluminum isopropoxide reduction in the industry at present can be avoided, three wastes are reduced, and the raw materials and reagents are cheap and readily available; 4-chlorobenzaldehyde is selected as a raw material, nitro substitution is adopted, and the generation of byproducts in nitration reaction is reduced; moreover, the method comprises a few synthesizing steps, the yield is high, and the method is more suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, be specifically related to a kind of method by 4-chlorobenzaldehyde synthesizing chloramphenicol.
Background technology
Catilan is a broad-spectrum antibiotics, is mainly used in Corynebacterium diphtheriae, and dysentery bacterium, meningococcus, pneumococcal infection also can be used for rickettsial infection.Although it has many spinoffs as suppressing the marrow hemopoiesis function, cause granular cell and thrombocytopenia or aplastic anemia, but still be the choice drug of treatment typhoid fever.
Paraxin is white or little yellowish green needle-like, the crystallization of lengthy motion picture shape or crystalline powder be with.Bitter.149～153 ℃ of fusing points.Be soluble in methyl alcohol, ethanol and acetone and other organic solvent, be slightly soluble in water.Specific optical rotation [α]
D 25=+18.5～+ 21.5 ° (absolute ethyl alcohol).
Synthetic route report about paraxin has a lot; But the domestic main synthesis technique that puts into production is to be starting raw material with ethylbenzene at present; Through oxidation, nitrated, bromination, ammonification, acetylize; The reduction of aldol condensation, aluminum isopropylate, chiral separation, polystep reaction such as two chloroacetylations makes paraxin then.Operational path is following:
Can find out from above; The synthetic route of paraxin is long at present, because the highest yield of theory that splits has only 50%, calculates with ethylbenzene; Domestic production is yield about 30% in fact; Make the production cost and the three wastes increase, the aluminum isopropylate reduction process also produces and is difficult to the three wastes handled in a large number, and therefore seeking more economical compound method is a challenge all the time.
Summary of the invention
The object of the invention is exactly for the synthetic of paraxin provides a kind of raw material to be easy to get, and avoids splitting, and cost is low, the preparation method that yield is high.
Preparing method of the present invention is following:
With the 4-chloro-benzaldehyde is starting raw material, and warp carries out asymmetric Henry reaction with the 2-nitroethyl alcohol, obtains (1R; 2R)-and 2-nitro-1-(4-chloro-phenyl-)-1, ammediol (II), catalytic hydrogenation is with the amino (1R that gets of nitroreduction then; 2R)-and 2-amino-1-(4-chloro-phenyl-)-1, ammediol (III), we find through experiment; Will (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, the amino of ammediol gets (1R through two chloroacetylations; 2R)-and 2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol (IV) is then at three (dibenzalacetone) two palladium [Pd
2(dba)
3] catalysis down and Sodium Nitrite react paraxin (I), like this, we just are controlled at four-step reaction with the synthetic route of paraxin.Bullion can obtain product, HPLC purity＞98.0% with high yield through recrystallization.Operational path is following:
Starting raw material also can be 4-bromobenzaldehyde, 4-benzaldehyde iodine.
The structure of catalyst ligand is following:
Document (Ma, K. are pressed in its preparation; You, J.Chem.Eur.J.2007,13,1863) method.
Obtained paraxin purity is greater than 98.0% according to the present invention, total recovery about 60%.Method yield of the present invention is high, and product purity meets the requirements, and can easily realize suitability for industrialized production, is a kind of preparation method that good suitability for industrialized production is worth that has.It is embodied in:
1) raw material is easy to get with inexpensive.
2) synthetic route is short, though document (Loncaric, C.; Wulff, W.D.Org.Lett., 2001,3675) reported that four of paraxin went on foot synthetic routes, but agents useful for same has paranitrobenzaldehyde, benzylamine and ethyl diazoacetate, and price is relatively costly, also has certain risk.
3) avoid fractionation and the use of aluminum isopropylate reductive agent in the synthetic route, solved a large amount of three wastes problems in the suitability for industrialized production.
4) total recovery is high, and total recovery is about 67%, is higher than 30% of existing technology far away.
What the present invention had innovation most is: the nitration reaction on the phenyl ring is very complicated; Often nitro does not have last to the position that needs; What perhaps obtain is many nitro-compounds, the present invention (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1; In the nitration reaction of ammediol, three (dibenzalacetone) two palladium [Pd have been adopted
2(dba)
3] make catalyzer, Sodium Nitrite is a nitrating agent, and nitration reaction is accurately located, and what reaction obtained basically is paraxin.
A kind of compound method of the present invention like the described paraxin of structural formula I: by (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol and Sodium Nitrite obtain paraxin through the nitro substitution reaction.
Structural formula I
(1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol through two chloroacetylations get (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol.
(1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol through the catalytic hydrogenation reduction obtain (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol.
With starting raw material 4-chloro-benzaldehyde and 2-nitroethyl alcohol is raw material, and synthetic obtaining in the presence of chiral catalyst (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol, starting raw material also can be 4-bromobenzaldehyde, 4-benzaldehyde iodine.
The nitro substitution reaction is with three (dibenzalacetone) two palladium [Pd
2(dba)
3] or palladium trifluoroacetate (Pd (OTFA)
2) be catalyzer,, the phosphorus part carries out under participating in.
Catalytic hydrogenation is a catalyzer with palladium carbon, preferentially selects 10% palladium carbon for use.
Chiral catalyst is prepared in dioxane with the chiral catalyst part by mantoquita or acetic acid rhodium.
Mantoquita comprises cupric chloride and copper trifluoromethanesulfcomposite (Cu (OTf)
2), the chiral catalyst part is 2,6-pair [(S)-and 4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine,
The phosphorus part comprises: 2-(di-t-butyl phosphine)-2 ', 4 ', 6 '-tri isopropyl biphenyl (t-BuXPhos), 2-di-t-butyl phosphorus-3; 4,5,6-tetramethyl--2 '; 4 ', 6 '-tri isopropyl biphenyl, 2-di-t-butyl phosphorus-3; 5-dimethoxy-2 ', at least a in 4 ', 6 '-tri isopropyl biphenyl (t-BuBrettPhos).(document J.AM.CHEM.SOC.209,131,12898-12899)
Embodiment
The following example is used for further narrating the present invention, but it is not any restriction to scope of the present invention.The purity testing of each compound is measured on the HP1100 high performance liquid chromatograph.
Embodiment 1 (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1,1 of the preparation of ammediol
With 1.8 gram Cu (OTf)
2(0.50mmol), 2.4 grams 2,6-two [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine (5.2mmol) with 40 milliliter 1, in 250 milliliters of single port flasks of 4-dioxane adding; With keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, under room temperature, magnetic agitation with the ice bath cooling, adds 7.0 gram 4-chlorobenzaldehydes (50mmol), (0.54 milliliter of 45.5 gram 2-nitroethyl alcohols (500mmol) and N-methylmorpholine after 2 hours successively; 5.0mmol), reaction solution stir about 24 hours in 0～5 ℃ of ice bath, after the thin plate chromatography detected no raw material 4-chlorobenzaldehyde spot, volatile solvent was removed in underpressure distillation then, through filtered through silica gel removal catalyzer; Filtrating concentrates to such an extent that product 10.6 restrains, yield 91.8%, and it is 93.5% that HPLC measures the e.e value, 1H NMR (acetone-d6) δ: 3.71 (s, 1H); 3.85 (m, 1H), 4.12 (m, 1H), 4.52 (m; 1H), 4.79 (m, 1H), 5.01 (d; J=8.7Hz, 1H), 7.15-7.26 (m, 4H).
Embodiment 2 (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1,2 of the preparation of ammediol
With 0.8 gram Cu (OTf)
2(0.50mmol), 0.8 gram acetic acid rhodium, 1.2 grams 2,6-two [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine (5.2mmol) and 20 milliliter 1; The 4-dioxane adds in 250 milliliters of single port flasks, and with keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, under room temperature, magnetic agitation with the ice bath cooling, adds 7.0 gram 4-chlorobenzaldehydes (50mmol) after 2 hours successively; 45.5 gram 2-nitroethyl alcohol (500mmol) and 0.15 gram picoline, reaction solution stir about 20 hours in 4 ℃ of ice baths, after the thin plate chromatography detected no raw material 4-chlorobenzaldehyde spot, volatile solvent was removed in underpressure distillation then, through filtered through silica gel removal catalyzer; Filtrating concentrates to such an extent that product 10.9 restrains, yield 92.8%, and it is 94.2% that HPLC measures the e.e value, 1H NMR (acetone-d6) δ: 3.71 (s, 1H); 3.85 (m, 1H), 4.12 (m, 1H), 4.52 (m; 1H), 4.79 (m, 1H), 5.01 (d; J=8.7Hz, 1H), 7.15-7.26 (m, 4H).
Embodiment 3 (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1,3 of the preparation of ammediol
With 1.8 gram Cu (OTf)
2(0.50mmol), 2.4 grams 2,6-two [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine (5.2mmol) with 40 milliliter 1, in 250 milliliters of single port flasks of 4-dioxane adding; With keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, under room temperature, magnetic agitation with the ice bath cooling, adds 6.0 gram 4-bromobenzaldehydes, (0.54 milliliter of 45.5 gram 2-nitroethyl alcohols (500mmol) and N-methylmorpholine after 2 hours successively; 5.0mmol), reaction solution stir about 30 hours in 4 ℃ of ice baths, after the thin plate chromatography detected no raw material 4-chlorobenzaldehyde spot, volatile solvent was removed in underpressure distillation then, through filtered through silica gel removal catalyzer; Filtrating concentrates to such an extent that product 9.6 restrains, yield 86.2%, and it is 92.9% that HPLC measures the e.e value, 1HNMR (acetone-d6) δ: 3.71 (s, 1H); 3.85 (m, 1H), 4.12 (m, 1H), 4.52 (m; 1H), 4.79 (m, 1H), 5.01 (d; J=8.7Hz, 1H), 7.15-7.26 (m, 4H).
Embodiment 4 (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1,4 of the preparation of ammediol
With 0.8 gram Cu (OTf)
2(0.50mmol), 0.8 gram acetic acid rhodium, 1.2 grams 2 are in 6-two [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] 250 milliliters of single port flasks of pyridine (5.2mmol) and 20 milliliters of ethylene dichloride addings; With keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, under room temperature, magnetic agitation with the ice bath cooling, adds 6.0 gram 4-benzaldehyde iodines after 2 hours successively, 45.5 gram 2-nitroethyl alcohols (500mmol) and 0.15 gram picoline; Reaction solution stir about 20 hours in 4 ℃ of ice baths, after the thin plate chromatography detected no raw material 4-chlorobenzaldehyde spot, volatile solvent was removed in underpressure distillation then, removed catalyzer through filtered through silica gel, and filtrating concentrates to such an extent that product 10.9 restrains; Yield 91.6%, it is 93.7% that HPLC measures the e.e value, 1H NMR (acetone-d6) δ: 3.71 (s, 1H), 3.85 (m; 1H), 4.12 (m, 1H), 4.52 (m; 1H), 4.79 (m, 1H), 5.01 (d; J=8.7Hz, 1H), 7.15-7.26 (m, 4H).
Embodiment 5 (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, the preparation of ammediol
With 5.8 grams (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, the preparation of ammediol (25mmol) is dissolved in 100 ml methanol; Add 0.1 gram, 10% palladium carbon catalyst; Catalytic hydrogenation under hydrogen pressure 0.2MPa, the thin plate chromatography detects no raw material spot after-filtration and removes catalyzer, and filtrating concentrates the back and gets product 4.6 grams with 1: 2.5 ethanol-acetone mixed solvent recrystallization; Yield 92.0%
1H?NMR(acetone-d
6)δ：3.45(m，1H)，3.72(s，1H)，3.92(m，1H)，4.17-4.22(m，2H)，4.82(m，1H)，5.05(d，J＝9.0Hz，1H)，5.02-5.09(m，1H)，7.18-7.31(m，4H)。
Embodiment 6 (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, the preparation of ammediol
With 4.5 grams (22mmol) (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol and 30 milliliters of methyl dichloroacetates (0.3mol) add in the single port flask successively, stirred 2 hours in 100～110 ℃, concentrating under reduced pressure behind the no raw material spot of thin plate chromatography detection, solid gets (1R with ETHYLE ACETATE and normal hexane mixed solvent recrystallization; 2R)-and 2-dichloro acetic acid formamido--1-(4-chloro-phenyl-)-1, ammediol 6.1 grams, yield 88.7%, 1H NMR (acetone-d6) δ: 3.74 (s, 1H), 3.91 (m; 1H), 4.19 (m, 1H), 4.22 (m, 1H), 4.75 (m; 1H), 5.01 (d, J=8.7Hz, 1H), 6.28 (s; 1H), 7.22-7.40 (m, 4H), 7.65 (s, 1H).
1 of the preparation of embodiment 7 paraxin
With 6 grams (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol (19mmol), 2.6 gram (38mmol) Sodium Nitrites, 0.09 gram (0.1mmol) three (dibenzalacetone), two palladium [Pd
2(dba)
3], 0.10 gram 2-(di-t-butyl phosphine)-2 ', 4 ', 6 '-tri isopropyl biphenyl (t-BuXPhos), the 45ml trimethyl carbinol add in the 100ml there-necked flask; 105～110 ℃ of reactions added in the single port flask in 10 hours, stirred concentrating under reduced pressure behind the no raw material spot of thin plate chromatography detection 2 hours in 100～110 ℃; Reaction solution concentrates, and, concentrates catalyst separating with silicagel column; Solid gets paraxin 5.4 gram with ETHYLE ACETATE and normal hexane mixed solvent recrystallization, yield 88%, m.p.147～149 °; Purity 98.6%, nuclear magnetic spectrum is consistent with standard diagram.
2 of the preparation of embodiment 8 paraxin
With 6 grams (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol (19mmol), 2.6 gram (38mmol) Sodium Nitrites, 0.05 gram (0.1mmol) palladium trifluoroacetate (Pd (OTFA)
2), 0.08 gram 2-di-t-butyl phosphorus-3,4,5,6-tetramethyl--2 '; 4 ', 6 '-tri isopropyl biphenyl, the 45ml trimethyl carbinol add in the 100ml there-necked flask, and 105～110 ℃ of reactions added in the single port flask in 10 hours, stirred 2 hours in 100～110 ℃; The thin plate chromatography detects concentrating under reduced pressure behind the no raw material spot, and reaction solution is concentrated, with silicagel column with catalyst separating; Concentrate, solid gets paraxin 5.5 grams, yield 89% with ETHYLE ACETATE and normal hexane mixed solvent recrystallization; M.p.147～149 °, purity 98.7%, nuclear magnetic spectrum is consistent with standard diagram.
Claims (9)
1. compound method like the described paraxin of structural formula I is characterized in that by (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol and Sodium Nitrite obtain paraxin through the nitro substitution reaction.
Structural formula I
2. method according to claim 1 is characterized in that: (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol through two chloroacetylations get (1R, 2R)-2-dichloro acetamide base-1-(4-chloro-phenyl-)-1, ammediol.
3. method according to claim 2 is characterized in that: (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol through the catalytic hydrogenation reduction obtain (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol.
4. method according to claim 3 is characterized in that: with 4-chloro-benzaldehyde and 2-nitroethyl alcohol is raw material, and synthetic obtaining in the presence of chiral catalyst (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol.
5. method according to claim 1 is characterized in that the nitro substitution reaction is with three (dibenzalacetone) two palladium [Pd
2(dba)
3] be catalyzer or palladium trifluoroacetate (Pd (OTFA)
2) be catalyzer,, the phosphorus part carries out under participating in.
6. method according to claim 3 is characterized in that: catalytic hydrogenation is a catalyzer with palladium carbon.
7. method according to claim 4 is characterized in that: chiral catalyst is prepared in dioxane by mantoquita or acetic acid rhodium and chiral catalyst part.
8. method according to claim 7 is characterized in that: mantoquita comprises cupric chloride and copper trifluoromethanesulfcomposite (Cu (OTf)
2), the chiral catalyst part is 2,6-pair [(S)-and 4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine.
9. method according to claim 5 is characterized in that: the phosphorus part comprises: 2-(di-t-butyl phosphine)-2 ', 4 ', 6 '-tri isopropyl biphenyl (t-BuXPhos); 2-di-t-butyl phosphorus-3,4,5,6-tetramethyl--2 '; 4 ', 6 '-tri isopropyl biphenyl, 2-di-t-butyl phosphorus-3; 5-dimethoxy-2 ', at least a in 4 ', 6 '-tri isopropyl biphenyl (t-BuBrettPhos).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017549A (en) * | 2017-12-07 | 2018-05-11 | 南通常佑药业科技有限公司 | A kind of preparation method of 1- aryl -2- amino -1,3- propanediol hydrochloride derivatives |
| CN110878024A (en) * | 2019-12-11 | 2020-03-13 | 四川大学 | Synthesis method of (1R,2R) -nitroalcohol compound |
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| GB743446A (en) * | 1952-08-22 | 1956-01-18 | Boehringer & Soehne Gmbh | Improvements in or relating to aromatic 2-aminoalkanediols-(1.3) |
| CN101941927A (en) * | 2010-09-28 | 2011-01-12 | 湖北美天生物科技有限公司 | Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol |
-
2011
- 2011-12-21 CN CN 201110432047 patent/CN102399162B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB743446A (en) * | 1952-08-22 | 1956-01-18 | Boehringer & Soehne Gmbh | Improvements in or relating to aromatic 2-aminoalkanediols-(1.3) |
| CN101941927A (en) * | 2010-09-28 | 2011-01-12 | 湖北美天生物科技有限公司 | Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017549A (en) * | 2017-12-07 | 2018-05-11 | 南通常佑药业科技有限公司 | A kind of preparation method of 1- aryl -2- amino -1,3- propanediol hydrochloride derivatives |
| CN110878024A (en) * | 2019-12-11 | 2020-03-13 | 四川大学 | Synthesis method of (1R,2R) -nitroalcohol compound |
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