CN1916011A - Intermediate of synthesized pirilmycin, preparation method and usage - Google Patents
Intermediate of synthesized pirilmycin, preparation method and usage Download PDFInfo
- Publication number
- CN1916011A CN1916011A CN 200610152953 CN200610152953A CN1916011A CN 1916011 A CN1916011 A CN 1916011A CN 200610152953 CN200610152953 CN 200610152953 CN 200610152953 A CN200610152953 A CN 200610152953A CN 1916011 A CN1916011 A CN 1916011A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- mixture
- pirlimycin
- nitro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to a new intermediate for synthesizing pirlimycin and its oreoaration method. High-purity pirlimycin can be prepared by catalytic hydrogenation of the intermediate. The method avoids the use of expensive Pt as the catalyst, and has such advantages as cheap and easily available raw materials, mild reaction conditions and high product quality, thus is suitable for mass production.
Description
Technical field
The invention belongs to pharmaceutical chemistry and organic chemistry filed, particularly, the present invention relates to as the formula (1) compound of a kind of general structure and synthetic, and be raw material, prepare the purposes of highly purified pirlimycin (Pirlimycin, 2) with this compound.
Background technology
Pirlimycin (Pirlimycin) is a kind of semisynthetic lincomycins, is antibacterials for animals.The chemistry of pirlimycin is called 6-(4-ethyl-suitable-2 (S)-piperidine formyl amino)-1-sulfo--7 (S)-chloro-6,7, the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala hydrochloride monohydrate.The synthetic method of known pirlimycin such as U.S. Pat 4278789A and J.Med.Chem.1984,27,216 is described, sees shown in the reaction formula (1):
Reaction formula (1)
Wherein, 6-amino-1-sulfo--7 (S)-chloro-6,7, the chemical structure of the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala (7-Cl-MTL) is shown below:
The chemical structure of 7-Cl-MTL
In the above-mentioned route, catalytic hydrogenating reduction 6-(4-ethyl-2-pyridine formamido group)-1-sulfo--7 (S)-chloro-6,7, in the pyridine ring reaction of the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala (B), bibliographical information is selected PtO for use
2Make catalyzer, and large usage quantity.Secondly, obtain pirlimycin (2) behind the shortening and do not have the mixture (1: 1, weight ratio) of the isomer (C) of anti-microbial effect, need just can obtain highly purified pirlimycin (2) through crystallization repeatedly, crystallization yield is lower.
The inventor finds a kind of intermediate formula (1) compound of effective preparation pirlimycin through research, and has researched and developed the novel method of a preparation pirlimycin, has finished the present invention thus.
Summary of the invention
The purpose of this invention is to provide the compound shown in a kind of formula (1):
In the formula (1): R is a hydrogen atom, nitro, halogen atom, C
1-6Alkyl, or C
1-6Alkoxyl group; On the piperidine ring, 2-, the absolute configuration of 4-bit substituent be (2S, 4R); This compound is the important intermediate compound of preparation pirlimycin.
Another object of the present invention has provided the method for preparation formula (1) compound.
It is raw material that another object of the present invention has provided with compound (1), by shortening, prepares the purposes of highly purified pirlimycin (Pirlimycin, 2).
According to the present invention, it is characterized in that providing the preparation method of a kind of formula (1) compound; Specifically, the preparation of formula (1) compound is to prepare by following steps:
Step 1:
With formula (3) compound
With its enantiomorph---formula (3 ') compound
Mixture be raw material, with isobutyl chlorocarbonate
After the reaction, obtain compound shown in formula (1) and the formula (4) with the 7-Cl-MTL condensation again
Mixture.
Step 2:
The mixture of step 1 gained formula (1) and formula (4) compound by the method for recrystallization, obtains formula (1) compound.
The invention is characterized in that in the above-mentioned formula, R is hydrogen atom, nitro, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group; Be preferably hydrogen atom and nitro; Nitro more preferably; Halogen atom is selected from fluorine, chlorine or bromine atom.
The invention is characterized in that in the preparation process of above-mentioned formula (1) compound, reaction raw materials is formula (3) compound and its enantiomorph---the mixture of formula (3 ') compound; Wherein, the content of formula (3) compound is 1% to 100%; Preferred 50% to 100%.
According to the present invention, in the preparation process of above-mentioned formula (1) compound, in the mixture of the crude product of being addressed---formula (1) and formula (4) compound, the purity (de% value) of formula (1) compound is by the decision of the content of compound (3), generally 1～99%.
The invention is characterized in, in the preparation process of above-mentioned formula (1) compound, the re-crystallization step of being addressed, be different with the crystallographic property of formula (4) compound according to formula (1) compound, by selecting suitable recrystallisation solvent for use, formula (1) compound preferential crystallization is come out, and formula (4) compound still is dissolved in the crystalline mother solution, thereby reaches isolating purpose.
More particularly, the invention is characterized in that the recrystallisation solvent of being addressed is the mixture of one or more organic solvent; Wherein, organic solvent is selected from C
1-C
4Fatty Alcohol(C12-C14 and C12-C18), aliphatic ketone (as acetone, butanone), ester class (as ethyl acetate, methyl acetate), aliphatic hydrocarbon (as normal hexane).Preferred solvent is ethyl acetate, acetone, methyl alcohol.
According to the present invention, compound (1) is applicable to preparation highly purified pirlimycin (Pirlimycin, 2).
Specifically, compound (1) is sloughed the protecting group on the nitrogen-atoms in the piperidine ring through catalytic hydrogenation reaction, obtains pirlimycin (2) crude product; Just can conveniently obtain highly purified pirlimycin by simple crystallization again, shown in reaction formula (2):
Reaction formula (2)
Wherein R is hydrogen atom, nitro, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group; Be preferably hydrogen atom and nitro; Nitro more preferably; Halogen atom is selected from fluorine, chlorine or bromine atom.
In the above-mentioned reaction, shortening carries out in the presence of metal catalyst.Specifically, can select 5% or 10% Pd/C for use is catalyzer, and in the presence of HCl, shortening is finished.
Wherein, the consumption of Pd/C is 5%～50% (weight) of compound shown in the formula (1), is preferably 5%～20% (weight).The consumption of HCl is 0.5～2.5 times (mol ratio) of compound shown in the formula (1), is preferably 0.9～1.2 times.Reaction can be carried out in the mixed solvent of methyl alcohol or methyl alcohol and water.Temperature of reaction is at 10～50 ℃, and optimum condition is 10～35 ℃.Hydrogenation pressure is 1～30atm, is preferably 1～10atm.
According to the present invention, the purity of the pirlimycin of above-mentioned reaction gained (2) crude product is generally more than 90%, even can reach more than 95%, and through recrystallization, purity can reach more than 98.5%, even more than 99.5%, crystallization yield is greater than 90%.
Compare with art methods, superiority of the present invention is:
1), can avoid a large amount of and use expensive PtO2 to do catalysis, the reaction conditions gentleness from formula (1) compound preparation pirlimycin (2); The purity of gained pirlimycin crude product is generally more than 90%.Behind this crude product primary crystallization, purity can reach more than 98.5%, and crystallization yield is suitable for suitability for industrialized production more than 90%.
2) from formula (3) compound and its enantiomorph---mixture synthesis type (1) compound of formula (3 ') compound, advantage such as have the raw material cheapness, be easy to get; Particularly in used mixture, the optical purity of formula (3) compound can reduce the consumption of 7-Cl-MTL in a large number greater than 50% o'clock, reduced raw materials cost, reduced waste.
Embodiment
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.Except as otherwise noted, the percentage ratio among the present invention is meant weight percentage.
Embodiment 1: racemize cis-N-is to the preparation (is raw material with racemize cis-4-ethyl-piperidines-2-formate hydrochlorate) of nitro carbobenzoxy-(Cbz)-4-ethyl-piperidines-2-formic acid (1: 1 mixture of 3-1 and 3 '-1)
Thermometer, dropping funnel are being housed, are reaching in the churned mechanically 1000ml four-hole bottle, add cis-4-ethyl-piperidines-2-formate hydrochlorate (racemic mixture) (38.7g, 0.2mol) and water (350ml), after the stirring and dissolving, be about 9 with the sodium hydroxide solution regulator solution pH value of 2N.Ice-water bath cools, and under the vigorous stirring, (the pH value of control reaction mixture is 8.5-9.5 for 51.7g, the sodium hydroxide solution of (150ml) solution of tetrahydrofuran (THF) 0.24mol) and 1N to drip nitrobenzyl chloroformate ester simultaneously.After dripping, reaction solution at room temperature continued to stir 30 minutes, and concentrating under reduced pressure is removed tetrahydrofuran (THF).Under the frozen water cooling, it is 9-10 that resistates is regulated the pH value with the sodium hydroxide solution of 2N, uses the isopropyl ether extracting twice again.Divide and go organic phase, it is 1-2 that water is regulated the pH value with concentrated hydrochloric acid again, uses twice of ethyl acetate extraction.Merge organic phase, anhydrous sodium sulfate drying; Concentrating under reduced pressure obtains oily matter 71.5g, and wherein the content of title compound (mixture of 3-1 and 3 '-1) is about 87%, and this oily matter is directly used in the next step.The oily matter that takes a morsel, after column chromatography is separated, the mixture of (3-1) and its optical antipode (3 '-1), hydrogen spectrum data are as follows:
1H?NMR(400MHz，CDCl
3)δ10.44(brs，1H)，8.23(d，J＝8.4Hz，2H)，7.53(d，J＝7.2Hz，2H)，5.30(s，2H)，4.57(t，J＝6.4Hz，1H)，3.76(brs，1H)，3.51(brs，1H)，2.13-2.07(m，1H)，1.98-1.94(m，1H)，1.86-1.79(m，1H)，1.63-1.59(m，1H)，1.52-1.46(m，1H)，1.40-1.36(m，2H)，0.96(t，J＝7.4Hz，3H)ppm。
Embodiment 2: the preparation of racemize cis-N-carbobenzoxy-(Cbz)-4-ethyl-piperidines-2-formic acid (1: 1 mixture of 3-2 and 3 '-2) (is raw material with racemize cis-4-ethyl-piperidines-2-formate hydrochlorate)
Method according to embodiment 1, with chloroformic acid benzyl ester (40.8g, 0.24mol) replace the nitrobenzyl chloroformate ester in the reference example 1, other condition is identical, obtain oily matter 59.8g, wherein the content of title compound (mixture of 3-2 and 3 '-2) is about 91%, and this oily matter is directly used in the next step.The oily matter that takes a morsel, after column chromatography is separated, the mixture of (3-2) and its optical antipode (3 '-2), hydrogen spectrum data are as follows:
1H?NMR(400MHz，CDCl
3)δ9.11(brs，1H)，7.41-7.31(m，5H)，5.22(s，2H)，4.56(t，J＝6.4Hz，1H)，3.74(brs，1H)，3.45(brs，1H)，2.09-2.05(m，1H)，1.98-1.92(m，1H)，1.88-1.75(m，1H)，1.63-1.57(m，1H)，1.49-1.44(m，1H)，1.43-1.36(m，2H)，0.93(t，J＝7.4Hz，3H)ppm。
Embodiment 3:cis-N-is to the preparation of nitro carbobenzoxy-(Cbz)-4-ethyl-piperidines-2-formic acid (is that cis-4 (R)-ethyl-piperidines-2 (S)-formic acid of 95% is raw material with optical purity)
In the 25mL there-necked flask, add cis-4-ethyl-piperidines-2-formic acid (in cis-4 (R)-ethyl-piperidines-2 (S)-formic acid, optical purity is 95%) (0.78g, 4.96mmol) and water (8mL), stirring 10 minutes, is about 9 with the solution of potassium carbonate regulator solution pH value of 1N.Ice-water bath cools, and under the vigorous stirring, (the pH value of control reaction mixture is 8.5-9.5 for 1.39g, the solution of potassium carbonate of (10ml) solution of acetone 6.45mmol) and 1N to drip nitrobenzyl chloroformate ester simultaneously.After dripping, reaction solution at room temperature continued to stir 30 minutes, and concentrating under reduced pressure is removed acetone.Under the frozen water cooling, it is 9-10 that resistates is regulated the pH value with the solution of potassium carbonate of 1N, uses chloroform extraction again twice.Divide and go organic phase, it is 1-2 that water is regulated the pH value with concentrated hydrochloric acid again, uses twice of ethyl acetate extraction.Merge organic phase, anhydrous sodium sulfate drying; Concentrating under reduced pressure obtains oily matter 1.71g, and wherein the content of title compound is about 88%, is directly used in the next step.The oily matter that takes a morsel, after column chromatography was separated, hydrogen spectrum data were identical with embodiment 1.
Embodiment 4:6-[N-is to nitro benzyloxy carbonyl-4 (R)-ethyl-suitable-2 (S)-piperidine formyl amino]-1-sulfo--7 (S)-chloro-6; 7; the preparation of the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala (1-1 is called for short N-to nitro benzyloxy carbonyl acyl group pirlimycin):
Thermometer, dropping funnel are housed, reach in the churned mechanically 1000ml four-hole bottle, under the nitrogen protection, add embodiment 1 gained oily matter 38.8g (content 87%; 0.10mol); exsiccant acetonitrile 300ml, and diisopropylethylamine 14.8g (0.115mol) stirred 10 minutes.Reaction solution cools to-15 ℃, adds isobutyl chlorocarbonate 15.1g (0.11mol) again, continues reaction 30 minutes.Add subsequently in advance heating for dissolving again refrigerative 7-Cl-MTL (27.1g, (water: acetone=1: 1,500ml), reaction solution slowly rises to room temperature to solution 0.1mol), stirring reaction 12 hours.The TLC detection reaction is evaporated to small volume with reaction solution after finishing, and adds ethyl acetate, uses saturated NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, deionized water wash; Anhydrous Na
2SO
4After the dry organic phase, concentrate.Resistates ethyl acetate---acetone mixed solvent heating for dissolving is separated out solid after the cooling, this solid is compound (1-1), freeze overnight.Suction filtration is collected solid, the washing with acetone that a little is ice-cold, and 40 ℃ of following vacuum-dryings get N-to nitro benzyloxy carbonyl acyl group pirlimycin (1-1) 23.5g, and yield is calculated as 39.8% with 7-Cl-MTL, fusing point: 191-192 ℃ (decomposition).
1H?NMR(400MHz，DMSO-d6)δ8.22(d，J＝8.2Hz，2H)，7.87(brs，1H)，7.68(d，J＝8.2Hz，2H)，5.28(m，1H)，5.18(d，J＝5.0Hz，1H)，5.06(d，J＝4.2Hz，1H)，4.68(d，J＝3.5Hz，1H)，4.52(m，1H)，4.37(t，J＝9.3Hz，1H)，4.01(m，2H)，3.90(m，1H)，3.68(brs，2H)，3.32(brs，2H)，2.05(s，3H)，1.99(m，1H)，1.78(m，1H)，1.60(s，1H)，1.48(brs，1H)，1.37-1.31(m，6H)，0.88(t，J＝7.1Hz，3H)ppm。
13C?NMR(133MHz，DMSO-d6)δ173.8，155.7，147.4，145.2，128.8，124.0，88.6，70.6，69.8，68.3，68.0，65.7，59.8，55.7，52.7，38.9，32.7，31.8，28.5，27.6，23.1，12.9，12.2。
Embodiment 5:6-[N-carbobenzoxy-(Cbz)-4 (R)-ethyl-suitable-2 (S)-piperidine formyl amino]-1-sulfo--7 (S)-chloro-6,7, the preparation of the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala (1-2 is called for short N-benzyloxy carbonyl acyl group pirlimycin)
Thermometer, dropping funnel are housed, reach in the churned mechanically 500mL four-hole bottle, under the nitrogen protection, (content 91%, 45mol), exsiccant acetonitrile 150ml, and triethylamine 5.1g (50mol) stirred 10 minutes to add embodiment 2 gained oily matter 14.4g.Reaction solution cools to-15 ℃, adds isobutyl chlorocarbonate 6.8g (49.3mmol), continues reaction 30 minutes.(12.2g, (water: acetone=1: 1,200ml), reaction solution slowly rises to room temperature to solution 45mmol), stirring reaction 16 hours to add 7-Cl-MTL subsequently.The TLC detection reaction is evaporated to small volume with reaction solution after finishing, and adds ethyl acetate, uses saturated NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, deionized water wash; Anhydrous Na
2SO
4After the dry organic phase, concentrate.Resistates methyl alcohol heating for dissolving is separated out solid after the cooling, this solid is compound (1-2), freeze overnight.Suction filtration is collected solid, the methanol wash that a little is ice-cold, and 40 ℃ of following vacuum-dryings get N-benzyloxy carbonyl acyl group pirlimycin (1-2) 6.89g, and yield is calculated as 28.1% with 7-Cl-MTL.Fusing point: 94-96 ℃ (decomposition).
1H?NMR(400MHz，DMSO-d6)δ7.39-7.31(m，5H)，6.45(d，J＝9.1Hz，1H)，5.38(d，J＝5.5Hz，1H)，5.23(d，J＝12.4Hz，1H)，5.15(d，J＝12.4Hz，1H)，4.67(q，J＝6.7Hz，1H)，4.31(brs，1H)，4.24(t，J＝9.5Hz，1H)，4.16-4.10(m，2H)，4.07(d，J＝9.9Hz，1H)，3.83(brs，1H)，3.70(brs，1H)，3.61(dd，J1＝J2＝3.1Hz，1H)，3.42(brs，1H)，2.17(s，3H)，2.06-1.99(m，1H)，1.98-1.86(m，1H)，1.73-1.65(m，1H)，1.60-1.43(m，4H)，1.37-1.25(m，5H)，0.96(m，3H)ppm。
Embodiment 6:N-is to the preparation (is raw material with embodiment 3 gained oily matter) of nitro benzyloxy carbonyl acyl group pirlimycin (1-1)
In the 50mL there-necked flask; under the nitrogen protection, add the oily matter 1.71g (cis-N-is about 88% to the content of nitro benzyloxy carbonyl acyl group 4 (R)-ethyl-piperidines-2 (S)-formic acid) of embodiment 3 gained, exsiccant acetonitrile 15ml; and triethylamine 0.47g (4.64mmol), stirring and dissolving.Reaction solution cools to-15 ℃, adds isobutyl chlorocarbonate 0.63g (4.62mmol), continues reaction 30 minutes.(1.2g, (water: acetone=1: 1,20ml), reaction solution slowly rises to room temperature to solution 4.42mmol), stirring reaction 12 hours to add 7-Cl-MTL subsequently.The TLC detection reaction is evaporated to small volume with reaction solution after finishing, and adds ethyl acetate, uses saturated NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, deionized water wash; Anhydrous Na
2SO
4After the dry organic phase, concentration residue ethyl acetate---acetone mixed solvent heating for dissolving is separated out solid after the cooling, and this solid is compound (1-1), freeze overnight.Suction filtration is collected solid, the washing with acetone that a little is ice-cold, and 40 ℃ of following vacuum-dryings get N-to nitro benzyloxy carbonyl acyl group pirlimycin (1-1) 2.11g, calculate with 7-Cl-MTL, and total recovery is 81.1%.
Embodiment 7:6-(4 (R)-ethyls-suitable-2 (S)-piperidine formyl amino)-1-sulfo--7 (S)-chloro-6,7, the preparation of the hot pyrans methylglycoside hydrochloride monohydrate of 8-three deoxidations-L-Su Shi-a-D-gala (2, pirlimycin)
In the 250ml hydrogenation still, add N-to nitro benzyloxy carbonyl acyl group pirlimycin (1-1,9.5g, 16mmol), methyl alcohol 160ml, 36% concentrated hydrochloric acid 1.3ml, (5%, 1.6g), hydrogenation is 6 hours under 2atm pressure, and raw material removes by filter catalyzer after disappearing for Pd/C.Filtrate concentrates, and obtains crude product.The mixed solvent of the water-soluble and methyl alcohol of crude product, activated carbon decolorizing, recrystallization.Filter, a little methanol wash of filter cake, vacuum-drying gets pirlimycin 6.1g, and yield is 86%.Fusing point: 210-211 ℃; HPLC purity is 99.5%, specific rotation: [a]
D 25+ 182 ° of (C=1, H
2O).
1H?NMR(400MHz，D
2O)δ5.34(d，J＝5.8Hz，1H)，4.55(q，J＝1.42，6.7Hz，1H)，4.39-4.26(m，2H)，4.08(m，1H)，3.95(dd，J＝3.2，12.7Hz，1H)，3.83(d，J＝3.0Hz，1H)，3.60(dd，J＝3.3，10.4Hz，1H)，3.45(m，1H)，3.05(td，J＝2.8，6.4Hz，1H)，2.27(d，1H)，2.13(s，3H)，1.95(d，1H)，1.63(brs，1H)，1.46-1.29(m，7H)，0.85(t，J＝7.5Hz，3H)ppm。
Embodiment 8: the preparation of pirlimycin (2)
In the 250ml hydrogenation still, and adding N-benzyloxy carbonyl acyl group pirlimycin (1-2,5.9g, 10.8mmol), and methyl alcohol 100ml, 36% concentrated hydrochloric acid 0.66ml, (10%, 1.5g), hydrogenation is 18 hours under the 5atm pressure, and raw material removes by filter catalyzer after disappearing for Pd/C.Filtrate concentrates, and obtains crude product.The mixed solvent of the water-soluble and methyl alcohol of crude product, activated carbon decolorizing, recrystallization.Filter, a little methanol wash of filter cake, vacuum-drying gets pirlimycin 3.1g, and yield is 83%, and HPLC purity is 99.1%, specific rotation: [a]
D 25+ 181 ° of (C=1, H
2O).
Claims (10)
1. the compound shown in the formula (1),
Wherein, R is hydrogen atom, nitro, halogen atom, C
1-6Alkyl, or C
1-6Alkoxyl group; On the piperidine ring absolute configuration of 2-, 4-bit substituent be (2S, 4R).
2. according to the compound of claim 1, it is selected from:
6-[N-carbobenzoxy-(Cbz)-4 (R)-ethyl-suitable-2 (S)-piperidine formyl amino]-1-sulfo--7 (S)-chloro-6,7, the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala; Or
6-[N-is to nitro carbobenzoxy-(Cbz)-4 (R)-ethyl-suitable-2 (S)-piperidine formyl amino]-1-sulfo--7 (S)-chloro-6,7, the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala.
3. the mixture with formula (3) compound and its enantiomorph formula (3 ') is a raw material, the method for formula (1) compound of preparation claim 1:
Wherein: R is a hydrogen atom, nitro, halogen atom, C
1-6Alkyl, or C
1-6Alkoxyl group, this method comprises the following steps:
Step 1:
Behind the mixture and isobutyl chlorocarbonate reaction with formula (3) and formula (3 '), again with 6-amino-1-sulfo--7 (S)-chloro-6,7, the hot pyrans methylglycoside of 8-three deoxidations-L-Su Shi-a-D-gala (7-Cl-MTL) reacts, and obtains the mixture of formula (1) compound and formula (4) compound;
Wherein: 7-Cl-MTL is:
Step 2:
With the mixture of step 1 gained formula (1) compound and formula (4) compound, obtain compound (1) by the recrystallization separation.
4. according to the method for claim 3, it is characterized in that the content of formula (3) compound is 1% to 100% in the mixture of formula (3) and its enantiomorph (3 ').
5. according to the method for claim 4, it is characterized in that the content of formula (3) compound is preferably 50% to 100% in the mixture of formula (3) and its enantiomorph (3 ').
6. according to the method for claim 4, its Chinese style (1) compound is that feedstock production obtains with formula (3) compound.
7. according to the method for one of claim 3-6, it is characterized in that recrystallization solvent is selected from C
1-C
4Fatty Alcohol(C12-C14 and C12-C18), acetone, butanone, ethyl acetate, methyl acetate, normal hexane, or their mixture.
8. according to the method for claim 7, it is characterized in that recrystallization solvent is selected from ethyl acetate, methyl alcohol or acetone, or their mixture.
9. be used for the purposes of the pirlimycin of preparation formula (2) according to formula (1) compound of claim 1, it is characterized in that, formula (1) compound sloughs by shortening that the protecting group on the nitrogen-atoms obtains pirlimycin in the piperidine ring, and reaction formula is as follows:
Wherein, R is hydrogen atom, nitro, halogen atom, C
1-6Alkyl, or C
1-6Alkoxyl group; On the piperidine ring absolute configuration of 2-, 4-bit substituent be (2S, 4R).
10. according to the purposes of claim 10, wherein shortening is to be catalyzer with 5% or 10% Pd/C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101529535A CN100404543C (en) | 2006-09-21 | 2006-09-21 | Intermediate of synthesized pirilmycin, preparation method and usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101529535A CN100404543C (en) | 2006-09-21 | 2006-09-21 | Intermediate of synthesized pirilmycin, preparation method and usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1916011A true CN1916011A (en) | 2007-02-21 |
| CN100404543C CN100404543C (en) | 2008-07-23 |
Family
ID=37737095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101529535A Active CN100404543C (en) | 2006-09-21 | 2006-09-21 | Intermediate of synthesized pirilmycin, preparation method and usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100404543C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101555223B (en) * | 2009-04-17 | 2011-06-01 | 北京化工大学 | Pirlimycin intermediate and preparation method thereof |
| CN106074384A (en) * | 2016-08-08 | 2016-11-09 | 甘肃新天马制药股份有限公司 | A kind of pirlimycin micellar preparation and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4278789A (en) * | 1979-11-23 | 1981-07-14 | The Upjohn Company | Lincomycin compounds |
| US4309533A (en) * | 1980-05-19 | 1982-01-05 | The Upjohn Company | Lincomycin compounds |
| US4310660A (en) * | 1980-05-19 | 1982-01-12 | The Upjohn Company | Lincomycin compounds |
| ATE69142T1 (en) * | 1987-05-19 | 1991-11-15 | Upjohn Co | PIRLIMYCIN GROWTH ENHANCER FOR MEAT-PRODUCING ANIMALS. |
| IT1311921B1 (en) * | 1999-04-13 | 2002-03-20 | Nicox Sa | PHARMACEUTICAL COMPOUNDS. |
-
2006
- 2006-09-21 CN CNB2006101529535A patent/CN100404543C/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101555223B (en) * | 2009-04-17 | 2011-06-01 | 北京化工大学 | Pirlimycin intermediate and preparation method thereof |
| CN106074384A (en) * | 2016-08-08 | 2016-11-09 | 甘肃新天马制药股份有限公司 | A kind of pirlimycin micellar preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100404543C (en) | 2008-07-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2003053929A1 (en) | Process for production of optically active cis-piperidine derivatives | |
| CA2902422C (en) | Sodium salt of (2s, 5r)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid and its preparation | |
| EP2368870A1 (en) | Process for producing optically active carboxylic acid | |
| CN100383121C (en) | Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| CA2497066C (en) | Process for the preparation of 13-cis-retinoic acid | |
| EP2914574B1 (en) | New process | |
| JPH0674243B2 (en) | Optically active atenolol salt with high optical purity and process for producing atenolol | |
| CN1916011A (en) | Intermediate of synthesized pirilmycin, preparation method and usage | |
| JP5585822B2 (en) | Method for producing optically active nipecotic acid derivative | |
| EP3653607A2 (en) | Process for the preparation of enantiomerically enriched 3-aminopiperidine | |
| CA2615832A1 (en) | Method for producing nebivolol | |
| JP2011006379A (en) | Method for recrystallizing {2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-3-[1-(diphenylmethyl)azetidin-3-yl]ester-5-isopropyl ester}(azelnidipine), isopropyl alcohol adduct of azelnidipine, and method for producing azelnidipine | |
| KR100495107B1 (en) | Optical separation method of 3- (para-chlorophenyl) -glutaramide | |
| JPWO2007099843A1 (en) | α, β-Unsaturated cyclohexanone derivative, method for producing the same, and method for producing the intermediate | |
| EP1670767B2 (en) | Resolution of a narwedine amide derivative | |
| CN108409731B (en) | Chiral resolution of aryl-substituted 1H-pyridine [3,4-b ] indole-3-carboxylic acid methyl ester | |
| CN1114612C (en) | Process for synthesizing long-acting rapin lactones | |
| JPH10291975A (en) | Piperidine derivative and its production | |
| CN1442407A (en) | Chemical resolution preparation method of optically pure fesufenadin and its hydrochloride salt | |
| KR101001646B1 (en) | Method of preparing r-+-lansoprazole and intermediate used therein | |
| US7375245B2 (en) | N-(4-oxo-butanoic acid) -L-amino acid-ester derivatives and methods of preparation thereof | |
| JP4093608B2 (en) | Process for producing optically active 2-phenoxypropionic acid | |
| JP2013119518A (en) | Method for producing (s)-2-benzyl-3-(cis-hexahydro-2-isoindonilylcarbonyl)benzyl propionate | |
| EP3943482A1 (en) | Process for the preparation of latanoprostene bunod and intermediate thereof and compositions comprising the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |