CN102399164B - Method for synthesizing chloramphenicol from nitromethane - Google Patents
Method for synthesizing chloramphenicol from nitromethane Download PDFInfo
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Abstract
The invention relates to a method for synthesizing a broad spectrum antibiotic of chloramphenicol. The method comprises the following steps of: synthesizing (R)-2-nitro-1-(4-chlorophenyl)ethanol by using p-chlorobenzaldehyde and nitromethane as raw materials in the presence of a chiral catalyst; reacting with formaldehyde to obtain (1R,2R)-2-nitro-1-(4-chlorophenyl)-1,3-propanediol, and performing catalytic hydrogenation to obtain (1R,2R)-2-amino-1-(4-chlorophenyl)-1,3-propanediol; and performing nitro substitution and dichloro acetylization 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, the raw materials and reagents are cheap and readily available, 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 the Nitromethane 99Min. synthesizing chloramphenicol.
Background technology
Catilan is 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 side effects as suppressing the marrow hemopoiesis function, cause granular cell and thrombocytopenia or aplastic anemia, but still be the choice drug for the treatment of 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 ° (dehydrated 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 as follows:
As can be seen from the above, the synthetic route of paraxin is long at present, because the highest yield of theory that splits has only 50%, calculate with ethylbenzene, domestic production is yield about 30% in fact, make 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 synthetic method is a challenge all the time.
Summary of the invention
Purpose of the present 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.
Preparation method of the present invention is as follows:
Be starting raw material with the 4-chloro-benzaldehyde, through carrying out asymmetric Henry reaction with Nitromethane 99Min., obtain (R)-2-nitro-1-(4-chloro-phenyl-) ethanol (II), obtain (1R with formaldehyde reaction then, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol (III), catalytic hydrogenation is with nitro promising amino (1R also, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol (IV), we found through experiments, with (1R, 2R)-and 2-amino-1-(4-chloro-phenyl-)-1, ammediol is with three (dibenzalacetone) two palladium [Pd
2(dba)
3] can get corresponding nitro thing (V) with the Sodium Nitrite reaction under the catalysis, with get paraxin (I) by the dichloro acetylize, like this, we just control the synthetic route of paraxin at four-step reaction.Crude product can obtain product, HPLC purity＞98.0% with high yield through recrystallization.
Operational path is as follows:
The structure of catalyst ligand is as follows:
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 50%.Method yield height of the present invention, 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 and is 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 in the synthetic route and the use of aluminum isopropylate reductive agent, solved a large amount of three wastes problems in the suitability for industrialized production.
4) total recovery height, total recovery is about 55%, is higher than 30% of domestic existing technology far away.
A kind of preparation method as the described paraxin of structural formula I of the present invention, this method comprises the steps:
Structural formula I
A) (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol replace through nitro and obtain (1R, 2R)-2-amino-1-(4-nitrophenyl)-1, ammediol;
B) by (1R, 2R)-2-amino-1-(4-nitrophenyl)-1, ammediol and methyl dichloroacetate reaction obtain paraxin.
(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.
Be raw material with (R)-2-nitro-1-(4-chloro-phenyl-) ethanol and formaldehyde, and synthetic obtaining (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol.
Be raw material with 4-chloro-benzaldehyde and Nitromethane 99Min., synthetic (R)-2-nitro-1-(4-chloro-phenyl-) ethanol that obtains in the presence of chiral catalyst.
In the aforesaid method: the nitro substitution reaction is with three (dibenzalacetone) two palladium [Pd
2(dba)
3], or Palladous chloride is catalyzer, carries out under the phosphorus part participates in, 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).
Catalytic hydrogenation is catalyzer with palladium carbon.
Chiral catalyst by: lewis acid catalyst and chiral catalyst part prepare in organic solvents such as dioxane.
Organic solvent is selected from dioxane, dimethyl sulfoxide (DMSO), N, dinethylformamide,
Lewis acid catalyst is selected from, cupric chloride, acetic acid rhodium, trifluoromethanesulfonic acid cuprous (CuOTf), copper trifluoromethanesulfcomposite (Cu (OTf)
2), or the tetrem nitrile closes the cuprous (Cu (MeCN) of phosphofluoric acid
4PF
6),
The chiral catalyst part is 2,6-two [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine, 1-[2-(4S)-4-R-4,5-dihydro-2-oxazoline-ethyl] piperidines.
Embodiment
The following example is used for further narration the present invention, but it is not any restriction to scope of the present invention.The purity testing of each compound is measured at the HP1100 high performance liquid chromatograph.
1 of the preparation of embodiment 1 (R)-2-nitro-1-(4-chloro-phenyl-) ethanol
With 1.8 gram copper trifluoromethanesulfcomposite Cu (OTf)
2(0.50mmol), 2.4 gram part { 2,6-pair [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine } (5.2mmol) and 40 milliliter 1, the 4-dioxane adds in 250 milliliters of single port flasks, with keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, magnetic agitation was cooled off with ice bath after 2 hours, add 7.0 gram 4-chloro-benzaldehydes (50mmol) successively, and 30.6 gram Nitromethane 99Min.s (500mmol) and N-methylmorpholine (0.54 milliliter, 5.0mmol), reaction solution stirred 24 hours in the ice bath cooling, after the thin plate chromatography detected no raw material 4-chloro-benzaldehyde spot, volatile solvent was removed in underpressure distillation then, removed catalyzer by filtered through silica gel, filtrate concentrates to such an extent that product 9.0 restrains, yield 90%, it is 96.5% that HPLC measures the e.e value, nuclear magnetic spectrum and document (Jin et al, J.Org.Chem., 2011,76,484-491) report is consistent.
2 of the preparation of embodiment 2 (R)-2-nitro-1-(4-chloro-phenyl-) ethanol
In 100 milliliters of single port flasks, add 0.5 gram 1-[2-(4S)-4-R-4,5-dihydro-2-oxazoline-ethyl] piperidines, 0.09 cuprous (CuOTf) 2 of gram trifluoromethanesulfonic acid, 40 milliliters of anhydrous dimethyl sulfoxide (DMSO), with keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, magnetic agitation was cooled off with ice bath after 3 hours, add 7.0 gram 4-chloro-benzaldehydes (50mmol) successively, and 30.6 gram Nitromethane 99Min.s (500mmol) and N-methylmorpholine (0.54 milliliter, 5.0mmol), reaction solution stirred 24 hours in the ice bath cooling, after the thin plate chromatography detected no raw material 4-chloro-benzaldehyde spot, volatile solvent was removed in underpressure distillation then, removed catalyzer by filtered through silica gel, filtrate concentrates to such an extent that product 9.1 restrains, yield 91%, it is 96.7% that HPLC measures the e.e value, nuclear magnetic spectrum and document (Jin et al, J.Org.Chem., 2011,76,484-491) report is consistent.
Embodiment 3 (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1,1 of the preparation of ammediol
40 milliliter 1, the 4-dioxane adds in 250 milliliters of single port flasks, with keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, magnetic agitation also adds 1.2 gram Paraformaldehyde 96s (40mmol) successively, 8.0 (0.44 milliliter of gram (R)-2-nitro-1-(4-chloro-phenyl-) ethanol (40mmol) and N-methylmorpholine, 4mmol), reaction solution stirred 24 hours in the ice bath cooling, after the thin plate chromatography detects no raw material (R)-2-nitro-1-(4-chloro-phenyl-) ethanol spot, volatile solvent is removed in underpressure distillation, purifies by filtered through silica gel, and filtrate concentrates to such an extent that product 4.0 restrains, yield 86%
1H NMR (acetone-d
6) 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-)-1,2 of the preparation of ammediol
40 milliliter 1, the 4-dioxane adds in 250 milliliters of single port flasks, with keeping nitrogen gas stream constant behind the air of nitrogen replacement the inside, magnetic agitation also adds 1.2 gram Paraformaldehyde 96s (40mmol) successively, 8.0 gram (R)-2-nitro-1-(4-chloro-phenyl-) ethanol (40mmol) and 0.25 gram picoline, reaction solution stirred 12 hours in the ice bath cooling, after the thin plate chromatography detects no raw material (R)-2-nitro-1-(4-chloro-phenyl-) ethanol spot, volatile solvent is removed in underpressure distillation, purify by filtered through silica gel, filtrate concentrates to such an extent that product 4.1 restrains yield 87%
1H NMR (acetone-d
6) 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, filtrate concentrates the back and gets product 4.6 grams, yield 92%, 1H NMR (acetone-d6) δ: 3.45 (m with 1: 2.5 ethanol-acetone mixed solvent recrystallization, 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), and 5.02-5.09 (m, 1H), 7.18-7.31 (m, 4H).
Embodiment 6 (1R, 2R)-2-amino-1-p-nitrophenyl-1, the preparation of ammediol
With 4.5 gram (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol (22mmol), 3.0 gram (44mmol) Sodium Nitrites, 0.1 gram (0.11mmol) three (dibenzalacetone) two palladiums [Pd2 (dba) 3], 0.11 gram phosphorus part: 2-(di-t-butyl phosphine)-2 ', 4 ', 6 '-tri isopropyl biphenyl (t-BuXPhos),, the 45ml trimethyl carbinol adds in the 100ml there-necked flask, 105～110 ℃ were reacted 10 hours, reaction solution concentrates, with silicagel column with catalyst separating, product 4.0 gram, yield 85.7%, m.p.141～143 °.Nuclear magnetic spectrum and document Hazra, B.G., Pore, V.S., Maybhate, S.P., Natekar, M.V.and Rao, A.S., Synfh.Commiin., 1989,19,1763 unanimities.
The preparation of embodiment 7 paraxin
With 3 gram (1R, 2R)-2-amino-1-p-nitrophenyl-1, ammediol (14mmol) adds in the single port flask successively with 20 milliliters of methyl dichloroacetates (0.2mol), in 100～110 ℃ of stirrings 2 hours, concentrating under reduced pressure behind the no raw material spot of thin plate chromatography detection, solid gets paraxin 4.1 grams with ethyl acetate and normal hexane mixed solvent recrystallization, yield 90%, m.p.147～149 °, purity 98.3%, nuclear magnetic spectrum is consistent with standard diagram.
Claims (5)
1. the preparation method as the described paraxin of structural formula I is characterized in that this method comprises the steps:
Structural formula I
A) (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol and Sodium Nitrite replace and obtain (1R, 2R)-2-amino-1-(4-nitrophenyl)-1, ammediol through nitro;
B) by (1R, 2R)-2-amino-1-(4-nitrophenyl)-1, ammediol and methyl dichloroacetate reaction obtain paraxin;
Wherein, the nitro substitution reaction is with three (dibenzalacetone) two palladium [Pd
2(dba)
3] be catalyzer, under participating in, the phosphorus part carries out, and the phosphorus part is: 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', the 6'-tri isopropyl biphenyl, 2-di-t-butyl phosphorus-3,5-dimethoxy-2', 4', at least a in the 6'-tri isopropyl biphenyl (t-BuBrettPhos).
2. method according to claim 1 is characterized in that: (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol obtains (1R, 2R)-2-amino-1-(4-chloro-phenyl-)-1, ammediol through the catalytic hydrogenation reduction.
3. method according to claim 2 is characterized in that: with (R)-2-nitro-1-(4-chloro-phenyl-) ethanol and formaldehyde is raw material, synthetic obtaining (1R, 2R)-2-nitro-1-(4-chloro-phenyl-)-1, ammediol.
4. method according to claim 3 is characterized in that: be raw material with 4-chloro-benzaldehyde and Nitromethane 99Min., and synthetic (the R)-2-nitro-1-(4-chloro-phenyl-that obtains in the presence of chiral catalyst) ethanol; Chiral catalyst by: lewis acid catalyst and chiral catalyst part prepare in organic solvent; Organic solvent is selected from dioxane, dimethyl sulfoxide (DMSO), N, dinethylformamide; Lewis acid catalyst is selected from, cupric chloride, acetic acid rhodium, trifluoromethanesulfonic acid cuprous (CuOTf), copper trifluoromethanesulfcomposite (Cu (OTf)
2), or the tetrem nitrile closes the cuprous (Cu (MeCN) of phosphofluoric acid
4PF
6); The chiral catalyst part is 2,6-two [(S)-4-sec.-propyl-1-phenyl-4,5-dihydro-1H-2-imidazolyl] pyridine, 1-[2-(4S)-4-R-4,5-dihydro-2-oxazoline-ethyl] piperidines.
5. method according to claim 2, it is characterized in that: catalytic hydrogenation is catalyzer with palladium carbon.
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| CN104815692A (en) * | 2015-04-03 | 2015-08-05 | 江苏省原子医学研究所 | Copper catalyst and composition thereof, and applications of copper catalyst and composition |
| CN104892424A (en) * | 2015-04-03 | 2015-09-09 | 江苏省原子医学研究所 | Nitrobenzene preparation method |
| WO2018086287A1 (en) * | 2016-11-11 | 2018-05-17 | 苏州引航生物科技有限公司 | Method for preparing chloramphenicol compound |
| 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 |
| CN113200875B (en) * | 2021-04-26 | 2022-06-21 | 复旦大学 | Micro-reaction system and method for continuously preparing 2-amino-1, 3-diol compound |
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 |
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2011
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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 |
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