CN1597674A - 1,3-di[N-(2-methoxy) phenyl] piperazine]-1- acetone hydrochloride and its preparation method and application - Google Patents
1,3-di[N-(2-methoxy) phenyl] piperazine]-1- acetone hydrochloride and its preparation method and application Download PDFInfo
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Abstract
A 1,3-bis[N-[N-(2-methoxy)phenyl]piperazinyl]-1-acetone hydrochloride, its preparing process, and its application in preparing medicine for treating blood cancer are disclosed.
Description
(1) technical field
The present invention relates to pipobroman derivative and synthetic method thereof and application, relate in particular to 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride and synthetic, purification process and application.
(2) background technology
Pipobroman (1; 4-[3-bromine propionyl] piperazine) can be used for the treatment of polycythemia vera, primary thrombocytosis; particularly can be used for traditional remedies is had the treatment of chemical sproof chronic myelocytic leukemia; be used widely in countries such as the U.S., France, Italy and Germany; once recorded in American Pharmacopeia 21,22 editions; but because its toxicity is bigger, main adverse reaction is the moderate bone marrow depression, no longer records from 23 editions beginnings of American Pharmacopeia.In order to seek the piperazines antitumor drug of high-efficiency low-toxicity, the pharmacy worker has done number of research projects both at home and abroad, attempts it to be carried out structural modification, in the hope of obtaining new antitumor drug in the active group that keeps pipobroman.For example, monoacyl piperazine, symmetry and the asymmetric pair of substituted-piperazinyl, two spiral shells, three piperazines, dithiocarbamates class etc.
Though pipobroman (pipobroman) still is used widely in countries such as Italy, France and Germany at present, but its toxic side effect is too big, patient stomachache, diarrhoea can occur in the process of taking, aplastic anemia, myeloproliferative disorder and acute hepatic disease appear in a few patients, and its main adverse reaction is the moderate bone marrow depression during heavy dose of the use, show as symptoms such as oligoleukocythemia, thrombopenia, patient's karyomit(e) occurs unusually simultaneously, long-term heavy dose of danger that the acute leukemia of causing is arranged of using.Therefore, the low piperazines medicine of development antitumour activity high toxicity is one of focus of at present domestic and international the world of medicine.With the pipobroman is lead compound, though design synthetic new compound has report, because of receiving the restriction of factors such as non-activity and toxicity size, does not still have the new anti-leukemia medicine that is born so far, brings benefit to the mankind to replace pipobroman.
Look into newly through authoritative institution's retrieval, do not see brand-new compound 1 at present both at home and abroad as yet with antitumour activity, 3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride and synthetic report thereof.
(3) summary of the invention
The objective of the invention is to solve the deficiencies in the prior art, provide a kind of 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride and synthetic, purification process and its application in the anti-leukemia medicine of preparation.
The compound that the present invention relates to is represented with following general formula (I):
Wherein: R
1=R
2Representative
Above-mentioned compound, its called after 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride, molecular formula is C
25H
37O
3N
4Cl
3, molecular weight is 547.5, fusing point is 99～101 ℃.(qualification result is seen accompanying drawing)
Of the present invention 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride is synthetic, purification process, comprise the steps:
(1) bromo-propionic acid, sulfur oxychloride and solvent benzol are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing above-mentioned β-bromo propionyl chloro again and insert in another reactor, add the chloroform soln of 1-(2-methoxyphenyl) piperazine under the stirring at room, and add triethylamine, stir 15 minutes post-heating and be back to and react completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, principal spot R
fValue is 0.7, does not have other reactant spot;
(3) with step (2) reacting liquid filtering, after filtrate was washed 1～3 time, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Get brown oily liquid product through column chromatography purification again;
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered, promptly get 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.
Above-claimed cpd chamber preparation by experiment, its method may further comprise the steps:
(1) 5～15g bromo-propionic acid, 5～15ml sulfur oxychloride and 5～15ml benzene are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing 2～7g β-bromo propionyl chloro again and insert in another reactor, add the chloroform soln of 15～25ml 1-(2-methoxyphenyl) piperazine under the stirring at room, and add 4～10ml triethylamine, stir 15 minutes post-heating and be back to and react completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, principal spot R
fValue is 0.7, does not have other reactant spot;
(3) with step (2) reacting liquid filtering, after filtrate was washed 1～3 time, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Get brown oily liquid product 5～10g, productive rate 87.5%～89.5% through column chromatography purification again;
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered, promptly get 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.
Column chromatography described in the above-mentioned steps (3) preferably adopts silicagel column, and eluent is a dehydrated alcohol.
Filtration described in above-mentioned steps (3) or (4) preferably adopts B to filter.
Above-claimed cpd building-up process reaction formula is as follows:
The present invention relates to 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride has vital role, possesses very big application and development prospect in the anti-leukemia medicine of preparation.
In order to understand the action effect of essence of the present invention and The compounds of this invention better; below with 1; 3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride (pipobroman derivative 4) and similar new synthetic pipobroman derivative 1; 4-two (3-pyrrolidone-base propionyl) piperazine (pipobroman derivative 1); 1; 4-two (3-(N-hexahydropyridine base) propionyl) piperazine (pipobroman derivative 2); 1-(2-methoxyphenyl)-4-(3-bromine propionyl) piperazine (pipobroman derivative 3) and the existing commercial anti-leukemia medicine CDDP of clinical usefulness (are cis-platinum; produce lot number: 9905006) by Qilu Pharmaceutical Factory.Carry out external activity screening experiment (K
562And L
1210Cell toxicant suppresses experiment), illustrate compound of the present invention to the restraining effect of blood cell with and application in the anti-leukemia medicine of preparation.
K
562And L
1210The preparation of cell: cultivate K with ordinary method
562(erythroleukemia), L
1210(mouse lymph leukemia) cell (draw from institute of Materia Medica,Chinese Academy of Medical Sciences, and in the freezing preservation of institute of Shandong Academy of Medical Sciences and use for many years), it is good and cell that be in logarithmic phase is standby to choose growth conditions.
Adopt conventional cell toxicant to suppress experiment and carry out the external activity screening, the antitumour activity of more above-mentioned four new compounds further determines 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-the anti-leukemia effect of 1-acetone hydrochloride.
1,2, No. 3 groups of pipobroman derivative and K in the process of the test
562, L
1210After the cell co-cultivation 48,72 hours, observe being subjected to each dosage group cell proliferation of reagent thing and form and quantity not to have considerable change.No. 4, pipobroman derivative and K
562, L
1210After the cell co-cultivation 48,72 hours, observe and suppressed by the cell proliferation of reagent thing group.
According to new drug preclinical study governing principle, cell toxicant suppresses experiment should calculate the IC that is subjected to the reagent thing
50Value.Because of in 1,2, No. 3 medicine in vitro tests processes of pipobroman derivative this two strains cell inhibiting (rate) effect all not being reached more than 50%, so can't calculate IC
50Value.Illustrate that 1,2, No. 3 derivatives of pipobroman are to K
562And L
1210Cell does not have obvious restraining effect, and it is not obvious that promptly described compound cell in vitro poison suppresses experiment effect.And the present invention relates to 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride but cell toxicant to suppress experiment effect obvious.Experiment is obtained No. 4 different concns medicines of pipobroman derivative to K
562And L
1210Cell inhibiting all has positive effect, and wherein 48 hours inhibiting rate of maximum concentration effect is respectively 81%, 71%; The inhibiting rate that acts on 72 hours is respectively 81%, 71%.Its IC
50Value is respectively 0.68,0.72,2.18,1.46ug/ml.
The above results sees Table 1, table 2, table 3, table 4.
Table 1. different concns medicine is to K
56248 hours inhibiting rate of cytosis (%) (n=3)
Group different concns medicine inhibiting rate (%) IC
50
100 20 4 0.8 0.16
CDDP(ug/ml) 86 83 80 64 57 0.48(ug/ml)
Pipobroman derivative 1 (ug/ml) 29.0 14.8 4.4 2.2 0-
Pipobroman derivative 2 (ug/ml) 12.6 10.3 2.2 0 0-
Pipobroman derivative 3 (ug/ml) 6.6 3.7 6.6 11.0 8.9-
Pipobroman derivative 4 (ul/ml) 81 82 82 84 64 0.68 (ul/ml)
Table 2. different concns medicine is to K
56272 hours inhibiting rate of cytosis (%) (n=3)
Group different concns medicine inhibiting rate (%) IC
50
100 20 4 0.8 0.16
CDDP(ug/ml) 83 84 83 79 67 0.026(ug/ml)
Pipobroman derivative 1 (ug/ml) 26.8 17.9 16.7 15.0 15.0-
Pipobroman derivative 2 (ug/ml) 15.6 9.5 9.5 4.4 6.7-
Pipobroman derivative 3 (ug/ml) 9.5 15.0 12.8 0 9.5-
Pipobroman derivative 4 (ul/ml) 81 84 82 78 63 0.72 (ul/ml)
Table 3. different concns medicine is to L
121048 hours inhibiting rate of cytosis (%) (n=3)
Group different concns medicine inhibiting rate (%) IC
50
100 20 4 0.8 0.16
CDDP(ug/ml) 70 64 66 56 50 0.89(ug/ml)
Pipobroman derivative 1 (ug/ml) 18.8 8.0 5.3 0 0-
Pipobroman derivative 2 (ug/ml) 6.0 10.0 14.7 10.0 3.3-
Pipobroman derivative 3 (ug/ml) 7.3 10.7 6.7 17.4 15.4-
Pipobroman derivative 4 (ul/ml) 71 73 73 66 46 2.18 (ul/ml)
Table 4. different concns medicine is to L
121072 hours inhibiting rate of cytosis (%) (n=3)
Group different concns medicine inhibiting rate (%) IC
50
100 20 4 0.8 0.16
CDDP(ug/ml) 76 75 74 66 66 0.60(ug/ml)
Pipobroman derivative 1 (ug/ml) 20.0 11.7 8.1 9.7 10.7-
Pipobroman derivative 2 (ug/ml) 8.7 8.7 5.6 3.1 5.6-
Pipobroman derivative 3 (ug/ml) 8.7 9.7 12.2 8.7 9.7-
Pipobroman derivative 4 (ul/ml) 71 74 74 67 61 1.46 (ul/ml)
In above-mentioned compound external activity screening experiment; though compound used therefor all is similar new synthetic pipobroman derivative; but but there were significant differences for its pharmacological effect; this explanation is in carrying out pipobroman derivative synthetic; the bromine propionyl group that has antitumour activity in theory; be not important as the imagination; the bilateral of pipobroman or one-sided replacement and substituent difference all can directly have influence on the antitumour activity of institute's synthetic compound in fact; the theory action that group characterizes must come objective proof, the effect that can not come inference institute synthetic compound only according to theoretical function with experiment.
Below in conjunction with four that use in the process of the present invention new synthetic compounds, compare with its synthetic route the influence to institute's synthetic compound antitumour activity of pipobroman derivative different side-draws generation and substituent difference is described.
The preparation (No. 1 compound) of (1) 1,4-two (3-pyrrolidone-base propionyl) piperazine
The preparation of No. 1 compound must be synthesized pipobroman (1,4-two (3-bromine propionyl) piperazine) earlier, refabrication pyrrolidone sodium, the synthetic then product that makes.The building-up reactions route is complicated, belongs to the bilateral substituent of pipobroman, and experiment shows that the antitumour activity of product is low.
The preparation (No. 2 compounds) of (2) 1,4-two (3-(N-hexahydropyridine base) propionyl) piperazine
The preparation of No. 2 compounds also must be synthesized pipobroman (1,4-two (3-bromine propionyl) piperazine) earlier, makes product with the hexahydropyridine reaction again.The building-up reactions route is complicated, belongs to the bilateral substituent of pipobroman, and experiment shows that the antitumour activity of product is low.
(3) preparation (No. 3 compounds) of 1-(2-methoxyphenyl)-4-(3-bromine propionyl) piperazine
No. 3 compound need not prepare pipobroman, only needs preparation β-bromo propionyl chloro, can make product with the reaction of 1-(2-methoxyphenyl) piperazine.Belong to the one-sided replacement of pipobroman, kept the bromine propionyl group that antitumour activity is arranged of opposite side, but experiment shows that antitumour activity is minimum relatively.
The preparation (No. 4 compounds) of (4) 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
No. 4 compound need not prepare pipobroman, only needs preparation β-bromo propionyl chloro, can make product with the reaction of 1-(2-methoxyphenyl) piperazine.Reaction conditions and No. 3 compounds are different.The bilateral that belongs to pipobroman replaces, though do not keep bromine propionyl group in synthetic, experiment shows that antitumour activity is the highest.So No. 4 compounds are core compounds of the present invention.
In the above-mentioned building-up process, the main chemical reagent mark of use is as follows:
Bromo-propionic acid: Shanghai chemical reagents corporation of CP Chinese Medicine group
1-(2-methoxyphenyl) piperazine: CP Tianjin chemical reagent one factory
Sulfur oxychloride: CP Tianjin chemical reagent one factory
Benzene: chemical reagent work of AR Qilu Petroleum Chemistry Co. Inst.
Trichloromethane: AR Chemical Inst., Shandong Prov.
Triethylamine: AR Tianjin City Chemical Agent Research Institute
Anhydrous magnesium sulfate: CP Tianjin extensively becomes chemical reagent company limited
Dehydrated alcohol: AR Tianjin Chemical Reagents Factory No.1
Below in conjunction with accompanying drawing to synthetic 1 of the present invention, 3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride is further elaborated.
(4) description of drawings
Fig. 1 is 1, the ultra-violet absorption spectrum of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
Fig. 2 is 1, the infrared absorption spectrum of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
Fig. 3-1 is 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
1The H-NMR spectrum
Fig. 3-2 (A, B) 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
1The local spectrum of amplifying of H-NMR
Fig. 3-3 1, the heavy water exchange of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
1The H-NMR spectrum
Fig. 4-1 is 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
1H-
1The Hcosy spectrum
Fig. 4-2 (A, B) is 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
1H-
1The local spectrum of amplifying of Hcosy
Fig. 5-1 (A, B) is 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
13The C-NMR spectrum
Fig. 5-2 is 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride DEPT spectrum
Fig. 5-3 is 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride HETCOR spectrum
Fig. 5-4 (A, B) 1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]]-the local spectrum of amplifying of HETCOR of 1-acetone hydrochloride
Fig. 6 is 1, the ESI-MS mass spectrum of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
(5) embodiment
(1) 10g bromo-propionic acid, 12ml sulfur oxychloride and 10ml benzene are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing 5g β-bromo propionyl chloro again and place the 50ml three-necked bottle, the chloroform soln that adds 20ml 1-(2-methoxyphenyl) piperazine under the stirring at room, and adding 7.0ml triethylamine, stirring 15 minutes post-heating refluxes, constantly adularescent crystal generation in the reaction process, reflux is to reacting completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, principal spot R
fValue is 0.7, and does not have other reactant spot, and expression reacts completely;
(3) step (2) reaction solution is filtered with B, after filtrate was washed 2 times, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Carry out column chromatography purification with silicagel column again, eluent is a dehydrated alcohol, makes brown oily liquid product 8.0g, productive rate 87.5%.
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered with B, promptly get finished product.Described finished product carries out structure through instruments such as ultra-violet absorption spectrum, infrared absorption spectrum, proton nmr spectra, carbon-13 nmr spectra, mass spectrums and identifies judgement, and molecular formula is C
25H
37O
3N
4Cl
3, molecular weight is 547.5, called after 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.Fusing point (capillary tube technique) is 99～101 ℃.The RP-HPLC method detects purity, and content is greater than 98%.Concrete appraising datum sees the following form.
1. ultra-violet absorption spectrum (UV) data (seeing Table 5)
Table 5.1, the UV spectrum data of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
Solvent λ max ε max absorption band
279.4nm 3.25×10
3 R
Ethanol 240.2nm 8.20 * 10
3B
208nm 3.11×10
4 E
2
0.1mol/L HCl 269.8nm 3.00 * 10
3R
201nm 1.76×10
4 E
2
236.4nm 1.38×10
4 R
0.1mol/L NaOH
216.8nm 1.52 * 10
4E
2Or K
2. infrared absorption spectrum (IR) data (seeing Table 6)
Table 6.1, the IR data of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
Wave number (cm
-1) the vibration mode peak belongs to by force
3394 υ
OH W -OH
3019 υ
=CHOn the W phenyl ring=C-H
2962 υ
as -CH3，υ
as -CH2 m -CH
3，-CH
2
2506～2346 amine salt sum of fundamental frequencies m (multiple absorption) salify signs
1662 υ
-c＝o VS -C＝O
1610 υ
-c=cS phenyl ring skeletal vibration
1500 υ
-CH=CHS phenyl ring skeletal vibration
1461 δ
-CH2 S -CH
2
1448 δ
CH3 as S -CH
3
1381 δ
CH3 s S -CH
2
1264 υ
C-N S -N-CH
2-
1016 υ
C-CM alicyclic ring-CH
2-CH
2-
757 γ
=CHThe adjacent disubstituted benzene of m
3. proton nmr spectra (
1H-NMR) data (seeing Table 7)
Table 7.1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
1The H-NMR data
Sequence number chemical shift (ppm) multiplicity proton number
1H-
1Hcosy
2 3.156 t 2 3.156；3.441
3 3.441 t 2 3.441；3.156
14，15 3.355～3.383 t 4 3.355～3.383；3.554～3.633
16，17 3.554～3.633 t 4 3.355～3.383；3.554～3.633
6，7 3.633～3.763 t 4 3.648～3.763；4.039～4.097
24 or 25 3.836 s 3 3.836
25 or 24 3.965 s 3 3.836
4，5 4.039～4.097 t 4 3.648～3.763；4.039～4.097
10 or 20 6.931～6.983 d 1 6.931～6.983; 7.105～7.153
13 or 23 7.038～7.067 d 1 7.038～7.067; 7.105～7.153
4. carbon-13 nmr spectra (
13C-NMR) data (seeing Table 8)
Table 8.1,3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
13The C-NMR data
Carbon sequence number chemical shift (ppm) carbon type HETCOR
2 26.901 2 * secondary carbon 3.642
3 51.536 2 * secondary carbon 3.441
4 or 5 38.400 secondary carbon 4.097～4.039
5 or 4 42.067 secondary carbon 4.097～4.039
14 or 15 47.037 secondary carbon 3.355～3.383
15 or 14 50.743 secondary carbon 3.355～3.383
6,7 or 16,17 52.054 2 * secondary carbon 3.582～3.763
16,17 or 6,7 52.100 2 * secondary carbon 3.582～3.763
24 or 25 55.453 primary carbons 3.836
25 or 24 56.441 primary carbons 3.965
13 or 23 112.234 tertiary carbons 7.043～7.067
23 or 13 113.852 tertiary carbons 7.313～7.340
10 or 20 118.902 tertiary carbons 7.105～7.153
20 or 10 120.812 tertiary carbons 6.934～6.983
11 or 21 121.152 tertiary carbons 7.105～7.153
21 or 11 122.366 tertiary carbons 7.971～7.945
12 or 22 124.745 tertiary carbons 7.105～7.153
22 or 12 130.621 tertiary carbons 7.480～7.532
8 or 18 129.860 quaternary carbons
18 or 8 137.419 quaternary carbons
9 or 19 151.760 quaternary carbons
19 or 9 151.922 quaternary carbons
1 167.800 carbonyl carbon
5. mass spectrum (ESI-MS) data (seeing Table 9)
Table 9.1, the ESI-MS data of 3-two [N-(N '-(2-methoxyl group) phenyl) piperazinyl]-1-acetone hydrochloride
Mass-to-charge ratio
The relative abundance fragmention
(m/z)
439.5 100％
(1) 7g bromo-propionic acid, 9ml sulfur oxychloride and 10ml benzene are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing 2.0g β-bromo propionyl chloro again and place the 50ml three-necked bottle, the chloroform soln that adds 15ml 1-(2-methoxyphenyl) piperazine under the stirring at room, and adding 4.0ml triethylamine, stirring 15 minutes post-heating refluxes, constantly adularescent crystal generation in the reaction process, reflux is to reacting completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, principal spot R
fValue is 0.7, and does not have other reactant spot, and expression reacts completely;
(3) step (2) reaction solution is filtered with B, after filtrate was washed 1 time, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Carry out column chromatography purification with silicagel column again, eluent is a dehydrated alcohol, makes brown oily liquid product 5.0g, productive rate 87.5%.
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered with B, promptly get finished product.Described finished product carries out structure through instruments such as ultra-violet absorption spectrum, infrared absorption spectrum, proton nmr spectra, carbon-13 nmr spectra, mass spectrums and identifies judgement, and molecular formula is C
25H
37O
3N
4Cl
3, molecular weight is 547.5, called after 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.Fusing point (capillary tube technique) is 99～101 ℃.The RP-HPLC method detects purity, and content is greater than 98%.
(1) 15g bromo-propionic acid, 15ml sulfur oxychloride and 15ml benzene are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing 7.0g β-bromo propionyl chloro again and place the 50ml three-necked bottle, the chloroform soln that adds 25ml 1-(2-methoxyphenyl) piperazine under the stirring at room, and adding 10ml triethylamine, stirring 15 minutes post-heating refluxes, constantly adularescent crystal generation in the reaction process, reflux is to reacting completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, principal spot R
fValue is 0.7, and does not have other reactant spot, and expression reacts completely;
(3) step (2) reaction solution is filtered with B, after filtrate was washed 3 times, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Carry out column chromatography purification with silicagel column again, eluent is a dehydrated alcohol, makes brown oily liquid product 10g, productive rate 87.5%.
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered with B, promptly get finished product.Described finished product carries out structure through instruments such as ultra-violet absorption spectrum, infrared absorption spectrum, proton nmr spectra, carbon-13 nmr spectra, mass spectrums and identifies judgement, and molecular formula is C
25H
37O
3N
4Cl
3, molecular weight is 547.5, called after 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.Fusing point (capillary tube technique) is 99～101 ℃.The RP-HPLC method detects purity, and content is greater than 98%.
Claims (7)
1. the compound of following general formula (I):
Wherein: R
1=R
2Representative
2. compound as claimed in claim 1, its called after 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride, molecular formula is C
25H
37O
3N
4Cl
3, molecular weight is 547.5, fusing point is 99～101 ℃.
3. the preparation method of claim 1 or 2 described compounds, this method may further comprise the steps:
(1) bromo-propionic acid, sulfur oxychloride and solvent benzol are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing above-mentioned β-bromo propionyl chloro again and insert in another reactor, add the chloroform soln of 1-(2-methoxyphenyl) piperazine under the stirring at room, and add triethylamine, stir 15 minutes post-heating and be back to and react completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, principal spot R
fValue is 0.7, does not have other reactant spot;
(3) with step (2) reacting liquid filtering, after filtrate was washed 1～3 time, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Get brown oily liquid product through column chromatography purification again;
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered, promptly get 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.
4. the preparation method of compound as claimed in claim 3, this compound prepared in laboratory may further comprise the steps:
(1) 5～15g bromo-propionic acid, 5～15ml sulfur oxychloride and 5～15ml benzene are added in the reactor successively, stir oil bath back flow reaction down, until reacting completely; Normal pressure steams down and desolventizes benzene and excessive SOCl
2, remove remaining SOCl then under reduced pressure
2, promptly get yellow liquid β-bromo propionyl chloro;
(2) take by weighing 2～7g β-bromo propionyl chloro again and insert in another reactor, add the chloroform soln of 15～25ml 1-(2-methoxyphenyl) piperazine under the stirring at room, and add 4～10ml triethylamine, stir 15 minutes post-heating and be back to and react completely; Index is used GF with the monitoring of TLC method
254Plate, developping agent are dehydrated alcohol, and principal spot Rf value is 0.7, do not have other reactant spot;
(3) with step (2) reacting liquid filtering, after filtrate was washed 1～3 time, with the chloroform layer anhydrous magnesium sulfate drying, placement was spent the night, and the evaporated under reduced pressure chloroform gets brown oil; Get brown oily liquid product 5～10g, productive rate 87.5%～89.5% through column chromatography purification again;
(4) above-mentioned oily product is dissolved in methylene dichloride after, in its solution, feed HCl gas and make its salify, the off-white color crystallization of separating out is filtered, promptly get 1,3-two [N-[N '-(2-methoxyl group) phenyl] piperazinyl]-1-acetone hydrochloride.
5. the preparation method of compound as claimed in claim 4, the column chromatography described in the step (3) adopts silicagel column, and eluent is a dehydrated alcohol.
6. the preparation method of compound as claimed in claim 4, the filtration described in step (3) or (4) adopts B to filter.
7. the application of any described compound in the anti-leukemia medicine of preparation in the claim 1～2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410024520 CN1264829C (en) | 2004-07-23 | 2004-07-23 | 1,3-di[N-(2-methoxy) phenyl] piperazine]-1- acetone hydrochloride and its preparation method and application |
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| CN1264829C CN1264829C (en) | 2006-07-19 |
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|---|---|---|---|---|
| CN111320561A (en) * | 2020-04-14 | 2020-06-23 | 山东京卫制药有限公司 | Preparation method of vortioxetine impurity |
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2004
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111320561A (en) * | 2020-04-14 | 2020-06-23 | 山东京卫制药有限公司 | Preparation method of vortioxetine impurity |
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