CN106749327A - Rifamycin-S crystal and preparation method thereof - Google Patents
Rifamycin-S crystal and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to chemical medicine, and in particular to rifamycin-S crystal and preparation method thereof.The technical problem to be solved in the present invention is that the purity of unformed rifamycin-S is relatively low, uses it that the high cost of downstream product is prepared for raw material, and also can produce a large amount of organic wastes, can bring huge environmental protection pressure.The scheme that the present invention solves above-mentioned technical problem is to provide the rifamycin-S crystal with crystal habit that a kind of prior art has no report.Present invention also offers the preparation method of above-mentioned rifamycin-S crystal.The downstream product for using the high-purity rifamycin-S of present invention offer to be prepared for raw material, such as rifaximin, it is not necessary to by being further purified the quality requirement that can just meet various pharmacopeia.
Description
Technical field
The invention belongs to chemical medicine, and in particular to rifamycin-S crystal and preparation method thereof.
Background technology
Rifamycin-S (Rifamycin S), entitled 5,17,19,21- tetrahydroxy -23- methoxyl group -2 of chemistry, 4,12,16,
18,20,22- hexamethyl -2,7- epoxies 15 carbon [1,11,13] triolefin imines) naphtho- [2,1-b] furans -1,6,9,11 (2H) -
Tetrone -21- acetic acid esters, its structure is as shown in Equation 1：
Rifamycin-S is a kind of rifamycin analog derivative, is a kind of important medicine intermediate.Rifamycin-S with not
Same side chain reaction, can respectively prepare the medicines such as rifampin, rifaximin, Mycobutin, Rifapentine.Rifamycin-S
Generally it is prepared using Mediterranean streptomycete fermentation product rifamycin B or fermentation oxidation product rifamycin-O, such as：It is beautiful
State patent application US3933801A discloses a kind of method that rifamycin-O prepares rifamycin-S：By rifamycin-O with dense
Hydrochloric acid is hydrolyzed, and the treatment of hydrolysate isopropanol obtains the rifamycin-S that purity is 98%, and this rifamycin-S is through X-ray
Powder diffraction is verified as a kind of unformed solid powder.Due to main component in the streptomycete fermentation product of Mediterranean content only
Only 90% or so, other compositions are the impurity such as protein, polysaccharide, therefore, it is this to be directly prepared by tunning and not
Rifamycin-S with crystal habit also inevitably contains more impurity, and purity is extremely difficult to more than 99%, causes to adopt
The downstream product prepared with this purity rifamycin-S not high is (such as：Rifampin, rifaximin, Mycobutin etc.), its quality
It is difficult to reach standards of pharmacopoeia requirement.Such as：The rifamycin-S without crystal habit that prior art is produced is used for raw material system
Standby rifaximin, product purity can only achieve 98.79%, and the impurity containing multiple more than 0.1% is tied again even across three times
Crystalline substance, its purity is also only capable of reaching 99.38%, and still containing the impurity more than 0.1%, meanwhile, yield is also reduced to only
48.2%, and consume substantial amounts of recrystallisation solvent.The method not only substantially increases product cost, also creates a large amount of organic
Discarded object, bring huge environmental protection pressure.
The content of the invention
The technical problem to be solved in the present invention is that the purity of unformed rifamycin-S is relatively low, uses it to be prepared for raw material
The high cost of downstream product, and also a large amount of organic wastes can be produced, huge environmental protection pressure can be brought.
The present invention solve above-mentioned technical problem scheme be to provide a kind of prior art have no report with crystal habit
Rifamycin-S crystal.
Above-mentioned rifamycin-S crystal on the X-ray powder diffraction spectrogram represented with 2 θ, 5.47 ± 0.20 °, 6.43
±0.20°、7.28±0.20°、7.96±0.20°、8.94±0.20°、10.39±0.20°、13.85±0.20°、14.46±
0.20°、15.82±0.20°、16.58±0.20°、17.24±0.20°、17.89±0.20°、18.02±0.20°、18.61
±0.20°、19.50±0.20°、20.99±0.20°、22.02±0.20°、23.28±0.20°、24.05±0.20°、
25.41 ± 0.20 °, 26.38 ± 0.20 °, 28.18 ± 0.20 °, 28.87 ± 0.20 °, 28.94 ± 0.20 ° have feature diffraction
Peak.
Above-mentioned rifamycin-S crystal on infrared spectrum, in 3465.55 ± 10cm-1、3378.47±10cm-1、
2966.30±10cm-1、2931.47±10cm-1、2873.41±10cm-1、2809.56±10cm-1、1737.61±10cm-1、
1699.54±10cm-1、1646.39±10cm-1、1599.47±10cm-1、1491.18±10cm-1、1455.07±10cm-1、
1415.10±10cm-1、1372.84±10cm-1、1322.95±10cm-1、1264.44±10cm-1、1198.57±10cm-1、
1175.13±10cm-1、1161.64±10cm-1、1125.50±10cm-1、1072.02±10cm-1、1020.29±10cm-1、
972.93±10cm-1、946.39±10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、
823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、729.06±10cm-1、
689.94±10cm-1、646.47±10cm-1、633.43±10cm-1、614.59±10cm-1、555.19±10cm-1、
532.01±10cm-1、476.95±10cm-1、432.03±10cm-1Place has characteristic absorption peak.
Above-mentioned rifamycin-S crystal use efficient liquid phase chromatographic analysis (normalization method), its chromatographic purity more than 99.9%,
And do not contain any impurity for being more than 0.1%.
Present invention also offers the preparation method of above-mentioned rifamycin-S crystal, the method is comprised the following steps：
A, rifamycin-S is dissolved in tetrahydrofuran；
B, addition acidic alumina are stirred 20~50 minutes, and alumina removed by filtration obtains tetrahydrofuran filtrate；
C, to hexamethylene is added in above-mentioned tetrahydrofuran filtrate, solid is collected by filtration, dry, obtain rifamycin-S crystal.
In the preparation method of above-mentioned rifamycin-S crystal, the volume weight of tetrahydrofuran described in step a and rifamycin-S
Than being 1~5 ︰ 1.
In above-mentioned preparation method, acidic alumina described in step b is 0.01~0.05 ︰ 1 with the weight ratio of rifamycin-S.
In above-mentioned preparation method, hexamethylene described in step c is 5~20 ︰ 1 with the volume ratio of tetrahydrofuran filtrate.
In above-mentioned preparation method, the mode of hexamethylene is added described in step c to be added dropwise.
The beneficial effects of the present invention are：The invention provides a kind of prior art have no report with crystal habit
Rifamycin-S crystal, with the chromatographic purity more than 99.9%, and does not contain any impurity more than 0.1%.Using this hair
The high-purity rifamycin-S of bright offer is downstream product prepared by raw material, such as rifaximin, it is not necessary to by being further purified
The quality requirement of various pharmacopeia can just be met.
Brief description of the drawings
Fig. 1：The X-ray powder diffraction collection of rifamycin-S prepared by comparative example 1.
Fig. 2：The X-ray powder diffraction collection of rifamycin-S crystal prepared by the present invention.
Fig. 3：The infrared spectrum of rifamycin-S prepared by comparative example 1.
Fig. 4：The infrared spectrum of rifamycin-S crystal prepared by the present invention.
Fig. 5：The HPLC-UV detection of rifamycin-S prepared by comparative example 1.
Fig. 6：The HPLC-UV detection of rifamycin-S crystal prepared by the present invention.
Fig. 7：Use the HPLC-UV detection of rifaximin of the rifamycin-S of the preparation of comparative example 1 prepared by raw material.
Fig. 8：Rifaximin of the rifamycin-S of the preparation of comparative example 1 prepared by raw material is used by after three recrystallizations
HPLC-UV detection.
Fig. 9：Use the efficient liquid phase figure of rifaximin of the rifamycin-S crystal of present invention preparation prepared by raw material
Spectrum.
Specific embodiment
The preparation method of rifamycin-S crystal, the method is comprised the following steps：
A, rifamycin-S is dissolved in tetrahydrofuran；
B, addition acidic alumina are stirred 20~50 minutes, and alumina removed by filtration obtains tetrahydrofuran filtrate；
C, to hexamethylene is added in above-mentioned tetrahydrofuran filtrate, solid is collected by filtration, dry, obtain rifamycin-S crystal.
In the preparation method of above-mentioned rifamycin-S crystal, the volume weight of tetrahydrofuran described in step a and rifamycin-S
Than being 1~5 ︰ 1.
In above-mentioned preparation method, acidic alumina described in step b is 0.01~0.05 ︰ 1 with the weight ratio of rifamycin-S.
In above-mentioned preparation method, hexamethylene described in step c is 5~20 ︰ 1 with the volume ratio of tetrahydrofuran filtrate.
In above-mentioned preparation method, the mode of hexamethylene is added described in step c to be added dropwise.
The invention provides rifamycin-S crystal with crystal habit and its preparation that a kind of prior art has no report
Method, below, present disclosure is further described by embodiment and accompanying drawing.
The preparation of the rifamycin-S of comparative example 1
With reference to the embodiment 1 in U.S. Patent application US3933801A, rifamycin-S is prepared for：By 450 grams of rifamycins
O is dissolved in 6430 milliliters of mixed solvents of Er Lv Jia Wan ︰ methyl alcohol=1 ︰ 1 (volume ratio), is kept for 18 DEG C and is stirred to solid dissolving,
Keep the temperature under agitation in 420 grams of concentrated hydrochloric acids are added dropwise in 30 minutes, continue to stir 20 minutes 1 hour after completion of dropping, with
Organic phase is evaporated, to residual with 300 milliliters of saturated sodium carbonate solutions, 300 milliliters of water, 300 milliliters of water washing organic phases successively afterwards
450 milliliters of isopropanols are added in excess, aqueous isopropanol is cooled to 0 DEG C, filtering, gained solid drying under reduced pressure obtains orange red
356.1 grams of the powdered rifamycin-S of color.Above solid liquid chromatogram purity (normalization method) is 98.85%, maximum single miscellaneous
Matter 0.27%, the impurity more than 0.1% has 3；X-ray powder diffraction spectrogram is without obvious characteristic peak；On infrared spectrum,
3480.13cm-1、2974.28cm-1、2938.89cm-1、2881.52cm-1、2815.36cm-1、1725.85cm-1、
1645.14cm-1、1567.23cm-1、1524.64cm-1、1458.77cm-1、1431.88cm-1、1391.30cm-1、
1375.23cm-1、1331.48cm-1、1295.65cm-1、1251.84cm-1、1183.80cm-1、1159.81cm-1、
1122.09cm-1、1098.55cm-1、1077.95cm-1、1060.70cm-1、1023.19cm-1、1000.22cm-1、974.68cm-1、946.48cm-1、896.59cm-1、842.03cm-1、808.40cm-1、792.75cm-1、773.66cm-1、734.78cm-1、
724.02cm-1、702.41cm-1、651.57cm-1、599.64cm-1、571.01cm-1、491.90cm-1、459.19cm-1、
405.60cm-1Place has characteristic absorption peak.
The preparation of the rifaximin of comparative example 2 and recrystallization
50 grams of rifamycin-S prepared by comparative example 1 is added in 80 milliliters of water and 80 milliliters of mixed solutions of ethanol,
Stirring adds 21.2 grams of 2-AMINO-4-PICOLINEs to after dissolving, and is warmed up to 50 DEG C and reacts 8 hours, cools to 30 DEG C, adds
1.5 grams of L-AAs are stirred 1 hour, are then cooled to 10 DEG C and are continued to stir 10 hours to the precipitation of rifaximin solid, filtering,
Solid is washed with the ethanol water mixed solution for being cooled to 0 DEG C, and drying under reduced pressure obtains 41.5 grams of rifaximin to constant weight.
Recrystallization：10 grams of the rifaximin is taken, heating for dissolving is subsequently added body in the ethanol that envelope-bulk to weight ratio is 2 ︰ 1
Product weight is cooled to 0 DEG C than the purified water for 4 ︰ 1, filters the solid for separating out, and is recrystallized again by above solvent ratios after drying
Twice, 4.82 grams of rifaximin is finally given.
The preparation of the rifamycin-S crystal of embodiment 1
10 grams of rifamycin-S prepared by comparative example 1 is added in 10 milliliters of tetrahydrofurans under agitation, treats that solid is complete
Portion dissolves, and adds 0.1 gram of acidic alumina to stir 30 minutes, filtering, to being slowly added dropwise total amount in filtrate for 50 milliliters under stirring
Hexamethylene, after starting to separate out solid, stopping is added dropwise and continues stirring and largely separated out to solid for 1 hour, continues thereafter with dropwise addition surplus
Remaining hexamethylene, stirs 5 hours after adding, filtering, and solid washs with a small amount of hexamethylene, drying under reduced pressure, obtain 9.58 grams it is scarlet
Color is crystallized, as rifamycin-S crystal.
The crystal has following characteristics：
On the X-ray powder diffraction spectrogram represented with 2 θ, 5.47 ± 0.20 °, 6.43 ± 0.20 °, 7.28 ±
0.20°、7.96±0.20°、8.94±0.20°、10.39±0.20°、13.85±0.20°、14.46±0.20°、15.82±
0.20°、16.58±0.20°、17.24±0.20°、17.89±0.20°、18.02±0.20°、18.61±0.20°、19.50
±0.20°、20.99±0.20°、22.02±0.20°、23.28±0.20°、24.05±0.20°、25.41±0.20°、
26.38 ± 0.20 °, 28.18 ± 0.20 °, 28.87 ± 0.20 °, 28.94 ± 0.20 ° have characteristic diffraction peak.
On infrared spectrum, in 3465.55 ± 10cm-1、3378.47±10cm-1、2966.30±10cm-1、2931.47
±10cm-1、2873.41±10cm-1、2809.56±10cm-1、1737.61±10cm-1、1699.54±10cm-1、1646.39
±10cm-1、1599.47±10cm-1、1491.18±10cm-1、1455.07±10cm-1、1415.10±10cm-1、1372.84
±10cm-1、1322.95±10cm-1、1264.44±10cm-1、1198.57±10cm-1、1175.13±10cm-1、1161.64
±10cm-1、1125.50±10cm-1、1072.02±10cm-1、1020.29±10cm-1、972.93±10cm-1、946.39±
10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、729.06±10cm-1、689.94±10cm-1、646.47±10cm-1、
633.43±10cm-1、614.59±10cm-1、555.19±10cm-1、532.01±10cm-1、476.95±10cm-1、
432.03±10cm-1Place has characteristic absorption peak.
Using efficient liquid phase chromatographic analysis (normalization method), chromatographic purity does not contain any being more than more than 99.9%
0.1% impurity.
The preparation of the rifamycin-S crystal of embodiment 2
10 grams of rifamycin-S prepared by comparative example 1 is added in 30 milliliters of tetrahydrofurans under agitation, treats that solid is complete
Portion dissolves, and adds 0.3 gram of acidic alumina to stir 30 minutes, filtering, to being slowly added dropwise total amount in filtrate for 300 milliliters under stirring
Hexamethylene, after starting to separate out solid, stopping is added dropwise and continues stirring and largely separated out to solid for 1 hour, continues thereafter with dropwise addition surplus
Remaining hexamethylene, stirs 5 hours after adding, filtering, and solid washs with a small amount of hexamethylene, drying under reduced pressure, obtain 9.13 grams it is scarlet
Color is crystallized, as rifamycin-S crystal.
The crystal has following characteristics：
On the X-ray powder diffraction spectrogram represented with 2 θ, on the X-ray powder diffraction spectrogram represented with 2 θ,
5.47±0.20°、6.43±0.20°、7.28±0.20°、7.96±0.20°、8.94±0.20°、10.39±0.20°、
13.85±0.20°、14.46±0.20°、15.82±0.20°、16.58±0.20°、17.24±0.20°、17.89±
0.20°、18.02±0.20°、18.61±0.20°、19.50±0.20°、20.99±0.20°、22.02±0.20°、23.28
±0.20°、24.05±0.20°、25.41±0.20°、26.38±0.20°、28.18±0.20°、28.87±0.20°、
28.94 ± 0.20 ° have characteristic diffraction peak.
On infrared spectrum, in 3465.55 ± 10cm-1、3378.47±10cm-1、2966.30±10cm-1、2931.47
±10cm-1、2873.41±10cm-1、2809.56±10cm-1、1737.61±10cm-1、1699.54±10cm-1、1646.39
±10cm-1、1599.47±10cm-1、1491.18±10cm-1、1455.07±10cm-1、1415.10±10cm-1、1372.84
±10cm-1、1322.95±10cm-1、1264.44±10cm-1、1198.57±10cm-1、1175.13±10cm-1、1161.64
±10cm-1、1125.50±10cm-1、1072.02±10cm-1、1020.29±10cm-1、972.93±10cm-1、946.39±
10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、729.06±10cm-1、689.94±10cm-1、646.47±10cm-1、
633.43±10cm-1、614.59±10cm-1、555.19±10cm-1、532.01±10cm-1、476.95±10cm-1、
432.03±10cm-1Place has characteristic absorption peak.
Using efficient liquid phase chromatographic analysis (normalization method), chromatographic purity does not contain any being more than more than 99.9%
0.1% impurity.
The preparation of the rifamycin-S crystal of embodiment 3
10 grams of rifamycin-S prepared by comparative example 1 is added in 50 milliliters of tetrahydrofurans under agitation, treats that solid is complete
Portion dissolves, and adds 0.5 gram of acidic alumina to stir 30 minutes, filtering, to total amount is slowly added dropwise in filtrate is 1000 millis under stirring
The hexamethylene for rising, after starting to separate out solid, stopping is added dropwise and continues stirring and largely separated out to solid for 1 hour, continues thereafter with dropwise addition
Remaining hexamethylene, stirs 5 hours after adding, filtering, and solid washs with a small amount of hexamethylene, drying under reduced pressure, obtain 7.83 grams it is fresh
Red colored crystalline, as rifamycin-S crystal.
The crystal has following characteristics：
On the X-ray powder diffraction spectrogram represented with 2 θ, on the X-ray powder diffraction spectrogram represented with 2 θ,
5.47±0.20°、6.43±0.20°、7.28±0.20°、7.96±0.20°、8.94±0.20°、10.39±0.20°、
13.85±0.20°、14.46±0.20°、15.82±0.20°、16.58±0.20°、17.24±0.20°、17.89±
0.20°、18.02±0.20°、18.61±0.20°、19.50±0.20°、20.99±0.20°、22.02±0.20°、23.28
±0.20°、24.05±0.20°、25.41±0.20°、26.38±0.20°、28.18±0.20°、28.87±0.20°、
28.94 ± 0.20 ° have characteristic diffraction peak.
On infrared spectrum, in 3465.55 ± 10cm-1、3378.47±10cm-1、2966.30±10cm-1、2931.47
±10cm-1、2873.41±10cm-1、2809.56±10cm-1、1737.61±10cm-1、1699.54±10cm-1、1646.39
±10cm-1、1599.47±10cm-1、1491.18±10cm-1、1455.07±10cm-1、1415.10±10cm-1、1372.84
±10cm-1、1322.95±10cm-1、1264.44±10cm-1、1198.57±10cm-1、1175.13±10cm-1、1161.64
±10cm-1、1125.50±10cm-1、1072.02±10cm-1、1020.29±10cm-1、972.93±10cm-1、946.39±
10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、729.06±10cm-1、689.94±10cm-1、646.47±10cm-1、
633.43±10cm-1、614.59±10cm-1、555.19±10cm-1、532.01±10cm-1、476.95±10cm-1、
432.03±10cm-1Place has characteristic absorption peak.
Using efficient liquid phase chromatographic analysis (normalization method), chromatographic purity does not contain any being more than more than 99.9%
0.1% impurity.
The preparation of the rifamycin-S crystal of embodiment 4
200 grams of rifamycin-S prepared by comparative example 1 is added in 200 milliliters of tetrahydrofurans under agitation, treats solid
All dissolvings, add 2 grams of acidic aluminas to stir 30 minutes, filtering, to total amount is slowly added dropwise in filtrate are 1000 millis under stirring
The hexamethylene for rising, after starting to separate out solid, stopping is added dropwise and continues stirring and largely separated out to solid for 1 hour, continues thereafter with dropwise addition
Remaining hexamethylene, stirs 5 hours after adding, filtering, and solid washs with a small amount of hexamethylene, drying under reduced pressure, obtain 192.8 grams it is fresh
Red colored crystalline, as rifamycin-S crystal.
The crystal has following characteristics：
On the X-ray powder diffraction spectrogram represented with 2 θ, on the X-ray powder diffraction spectrogram represented with 2 θ,
5.47±0.20°、6.43±0.20°、7.28±0.20°、7.96±0.20°、8.94±0.20°、10.39±0.20°、
13.85±0.20°、14.46±0.20°、15.82±0.20°、16.58±0.20°、17.24±0.20°、17.89±
0.20°、18.02±0.20°、18.61±0.20°、19.50±0.20°、20.99±0.20°、22.02±0.20°、23.28
±0.20°、24.05±0.20°、25.41±0.20°、26.38±0.20°、28.18±0.20°、28.87±0.20°、
28.94 ± 0.20 ° have characteristic diffraction peak.
On infrared spectrum, in 3465.55 ± 10cm-1、3378.47±10cm-1、2966.30±10cm-1、2931.47
±10cm-1、2873.41±10cm-1、2809.56±10cm-1、1737.61±10cm-1、1699.54±10cm-1、1646.39
±10cm-1、1599.47±10cm-1、1491.18±10cm-1、1455.07±10cm-1、1415.10±10cm-1、1372.84
±10cm-1、1322.95±10cm-1、1264.44±10cm-1、1198.57±10cm-1、1175.13±10cm-1、1161.64
±10cm-1、1125.50±10cm-1、1072.02±10cm-1、1020.29±10cm-1、972.93±10cm-1、946.39±
10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、729.06±10cm-1、689.94±10cm-1、646.47±10cm-1、
633.43±10cm-1、614.59±10cm-1、555.19±10cm-1、532.01±10cm-1、476.95±10cm-1、
432.03±10cm-1Place has characteristic absorption peak.
Using efficient liquid phase chromatographic analysis (normalization method), chromatographic purity does not contain any being more than more than 99.9%
0.1% impurity.
The preparation of the rifaximin of embodiment 5
50 grams of rifamycin-S prepared by embodiment 4 is added in 80 milliliters of water and 80 milliliters of mixed solutions of ethanol,
Stirring adds 21.2 grams of 2-AMINO-4-PICOLINEs to after dissolving, and is warmed up to 50 DEG C and reacts 8 hours, cools to 30 DEG C, adds
1.5 grams of L-AAs are stirred 1 hour, are then cooled to 10 DEG C and are continued to stir 10 hours to the precipitation of rifaximin solid, filtering,
Solid is washed with the ethanol water mixed solution for being cooled to 0 DEG C, and drying under reduced pressure obtains 42.1 grams of rifaximin to constant weight.
The X-ray diffraction experiment of the rifamycin-S of embodiment 6
Rifamycin-S prepared by comparative example 1 and embodiment 1 as sample, using X ' Pert Pro MRD X-rays
Diffractometer (PANalytical, Netherland) is tested, and Cu K α 1 are radiated (0.154056nm), graphite monochromator, pipe electricity
Pressure 40kV, tube current 40mA, 23 ° of θ sweep limits~50 °, 0.01 °/s of sweep speed, 0.01 ° of step-length has obtained rifamycin-S
X-ray diffracting spectrum (accompanying drawing：Fig. 1, Fig. 2).
As seen from Figure 1, Figure 2：Rifamycin-S prepared by comparative example 1 does not have obvious characteristic diffraction peak, is that a kind of nothing is fixed
The form of type and amorphous state.Rifamycin-S prepared by embodiment 1 is in the X-ray powder diffraction spectrogram represented with 2 θ
On, 5.47 °, 6.43 °, 7.28 °, 7.96 °, 8.94 °, 10.39 °, 13.85 °, 14.46 °, 15.82 °, 16.58 °, 17.24 °,
17.89°、18.02°、18.61°、19.50°、20.99°、22.02°、23.28°、24.05°、25.41°、26.38°、28.18°、
28.87 °, 28.94 ° have characteristic diffraction peak, are that a kind of prior art has no that the rifamycin-S with crystal habit of report is brilliant
Body.
The rifamycin-S infrared spectrum analysis of embodiment 7 is tested
Rifamycin-S prepared by comparative example 1 and embodiment 1 as sample, using SPECTRUM ONE (Perkin-
Elmer) infrared spectrometer is tested, pressing potassium bromide troche.Infrared spectrum (the accompanying drawing of rifamycin-S is obtained：Fig. 3, Fig. 4),
From Fig. 3, Fig. 4：Rifamycin-S prepared by comparative example 1 is in 3480.13cm-1、2974.28cm-1、2938.89cm-1、
2881.52cm-1、2815.36cm-1、1725.85cm-1、1645.14cm-1、1567.23cm-1、1524.64cm-1、
1458.77cm-1、1431.88cm-1、1391.30cm-1、1375.23cm-1、1331.48cm-1、1295.65cm-1、
1251.84cm-1、1183.80cm-1、1159.81cm-1、1122.09cm-1、1098.55cm-1、1077.95cm-1、
1060.70cm-1、1023.19cm-1、1000.22cm-1、974.68cm-1、946.48cm-1、896.59cm-1、842.03cm-1、
808.40cm-1、792.75cm-1、773.66cm-1、734.78cm-1、724.02cm-1、702.41cm-1、651.57cm-1、
599.64cm-1、571.01cm-1、491.90cm-1、459.19cm-1、405.60cm-1Place has characteristic absorption peak.
Rifamycin-S prepared by embodiment 1 is in 3465.55 ± 10cm-1、3378.47±10cm-1、2966.30±
10cm-1、2931.47±10cm-1、2873.41±10cm-1、2809.56±10cm-1、1737.61±10cm-1、1699.54±
10cm-1、1646.39±10cm-1、1599.47±10cm-1、1491.18±10cm-1、1455.07±10cm-1、1415.10±
10cm-1、1372.84±10cm-1、1322.95±10cm-1、1264.44±10cm-1、1198.57±10cm-1、1175.13±
10cm-1、1161.64±10cm-1、1125.50±10cm-1、1072.02±10cm-1、1020.29±10cm-1、972.93±
10cm-1、946.39±10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、729.06±10cm-1、689.94±10cm-1、
646.47±10cm-1、633.43±10cm-1、614.59±10cm-1、555.19±10cm-1、532.01±10cm-1、
476.95±10cm-1、432.03±10cm-1Place has characteristic absorption peak.
The infrared spectrum of the rifamycin-S prepared by visual contrast example 1 and embodiment 1 is differed, and illustrates its crystal habit
It is different.
The rifamycin-S liquid chromatogram purity of embodiment 8 is tested
Rifamycin-S prepared by comparative example 1 and embodiment 1 determines liquid chromatogram purity, chromatogram respectively as sample
System and chromatographic condition are as follows：Liquid chromatograph：Shimadzu LC-15；Chromatographic column：4.6*250mm C18 posts；Mobile phase：Yi Jing ︰ water
(being adjusted to pH7.2 containing 3.16 g/l of ammonium formate and with ammoniacal liquor)=63 ︰ 37；Flow velocity：1.4 ml/mins；Sample size：20 is micro-
Rise；Sample introduction concentration：5 mg/mls；Detection wavelength：276nm.The liquid-phase chromatographic analysis knot of rifamycin-S prepared by comparative example 1
Fruit is shown in Table 1, and the liquid-phase chromatographic analysis of the rifamycin-S prepared by embodiment 1 the results are shown in Table 2.
The liquid-phase chromatographic analysis result (normalization method) of rifamycin-S prepared by 1 comparative example of table 1
The liquid-phase chromatographic analysis result (normalization method) of rifamycin-S prepared by 2 embodiment of table 1
| Peak number | Retention time (minute) | Peak area | Content |
| 1 | 4.512 | 2104.184 | 0.0052 |
| 2 | 5.732 | 5988.831 | 0.0148 |
| 3 | 8.132 | 1982.788 | 0.0049 |
| 4 | 8.505 | 2913.485 | 0.0072 |
| 5 | 9.625 | 3844.182 | 0.0095 |
| 6 | 13.945 | 40437352.000 | 99.9315 |
| 7 | 17.525 | 5584.180 | 0.0138 |
| 8 | 20.318 | 1254.416 | 0.0031 |
| 9 | 23.572 | 1133.022 | 0.0028 |
| Amount to | 40465070.573 | 100.0000 |
From table 1, table 2, rifamycin-S chromatographic purity prepared by comparative example 1 is 98.85%, maximum single impurity
0.27%, the impurity more than 0.1% has 3.And rifamycin-S chromatographic purity prepared by embodiment 1 is 99.93%, is not contained
Impurity more than 0.1%.
The rifaximin liquid chromatogram purity of embodiment 9 is tested
Rifaximin prepared by comparative example 2 and embodiment 5 determines liquid chromatogram purity, chromatogram respectively as sample
System and chromatographic condition are as follows：Liquid chromatograph：Shimadzu LC-15；Chromatographic column：4.6*250mm C18 posts；Mobile phase：Yi Jing ︰ water
(being adjusted to pH7.2 containing 3.16 g/l of ammonium formate and with ammoniacal liquor)=63 ︰ 37；Flow velocity：1.4 ml/mins；Sample size：20 is micro-
Rise；Sample introduction concentration：5 mg/mls；Detection wavelength：276nm.
The liquid-phase chromatographic analysis of rifaximin prepared by comparative example 2 the results are shown in Table 3, and comparative example 2 recrystallizes the profit after three times
Good fortune former times bright liquid-phase chromatographic analysis the results are shown in Table 4, and the liquid-phase chromatographic analysis of the rifaximin prepared by embodiment 5 the results are shown in Table 5.
The liquid-phase chromatographic analysis result (normalization method) of rifaximin prepared by 3 comparative example of table 2
4 comparative example of table 2 recrystallizes the liquid-phase chromatographic analysis result (normalization method) of the rifaximin after three times
| Peak number | Retention time (minute) | Peak area | Content |
| 1 | 6.692 | 146465.400 | 0.2700 |
| 2 | 7.042 | 81857.885 | 0.1509 |
| 3 | 7.983 | 28859.108 | 0.0532 |
| 4 | 9.102 | 27890.869 | 0.0438 |
| 5 | 10.715 | 3417.526 | 0.0063 |
| 6 | 14.590 | 53907784.000 | 99.3757 |
| 7 | 18.843 | 54300.691 | 0.1001 |
| Amount to | 54246444.553 | 100 |
The liquid-phase chromatographic analysis result (normalization method) of rifaximin prepared by 5 embodiment of table 5
| Peak number | Retention time (minute) | Peak area | Content |
| 1 | 3.592 | 1547.920 | 0.0023 |
| 2 | 6.452 | 4980.263 | 0.0074 |
| 3 | 7.092 | 2019.025 | 0.0030 |
| 4 | 8.012 | 807.610 | 0.0012 |
| 5 | 8.858 | 7066.590 | 0.0105 |
| 6 | 10.765 | 1615.220 | 0.0024 |
| 7 | 15.192 | 67279856.000 | 99.9688 |
| 8 | 18.858 | 1547.919 | 0.0023 |
| 9 | 21.472 | 1413.320 | 0.0021 |
| Amount to | 67300853.866 | 100.0000 |
From table 3, table 4, table 5, rifaximin chromatographic purity prepared by comparative example 2 is 98.79%, even across three times
Recrystallization, its chromatographic purity also only has 99.38%, and still contains the impurity more than 0.1%.And profit prepared by embodiment 5
Good fortune former times is bright need not to be purified, and its chromatographic purity is 99.97%, be not contain more than 0.1% impurity, and relevant material is limited the quantity and meets Europe
The requirement of continent pharmacopeia.
Claims (8)
1. rifamycin-S crystal, it is characterised in that：On the X-ray powder diffraction spectrogram represented with 2 θ, 5.47 ±
0.20°、6.43±0.20°、7.28±0.20°、7.96±0.20°、8.94±0.20°、10.39±0.20°、13.85±
0.20°、14.46±0.20°、15.82±0.20°、16.58±0.20°、17.24±0.20°、17.89±0.20°、18.02
±0.20°、18.61±0.20°、19.50±0.20°、20.99±0.20°、22.02±0.20°、23.28±0.20°、
24.05±0.20°、25.41±0.20°、26.38±0.20°、28.18±0.20°、28.87±0.20°、28.94±0.20°
With characteristic diffraction peak.
2. rifamycin-S crystal according to claim 1, it is characterised in that：On infrared spectrum, 3465.55 ±
10cm-1、3378.47±10cm-1、2966.30±10cm-1、2931.47±10cm-1、2873.41±10cm-1、2809.56±
10cm-1、1737.61±10cm-1、1699.54±10cm-1、1646.39±10cm-1、1599.47±10cm-1、1491.18±
10cm-1、1455.07±10cm-1、1415.10±10cm-1、1372.84±10cm-1、1322.95±10cm-1、1264.44±
10cm-1、1198.57±10cm-1、1175.13±10cm-1、1161.64±10cm-1、1125.50±10cm-1、1072.02±
10cm-1、1020.29±10cm-1、972.93±10cm-1、946.39±10cm-1、914.52±10cm-1、894.23±10cm-1、875.39±10cm-1、823.90±10cm-1、787.01±10cm-1、768.18±10cm-1、744.99±10cm-1、
729.06±10cm-1、689.94±10cm-1、646.47±10cm-1、633.43±10cm-1、614.59±10cm-1、
555.19±10cm-1、532.01±10cm-1、476.95±10cm-1、432.03±10cm-1Place has characteristic absorption peak.
3. rifamycin-S crystal according to claim 1, it is characterised in that：Using efficient liquid phase chromatographic analysis, the profit
The chromatographic purity of good fortune mycin S crystal does not contain any impurity for being more than 0.1% more than 99.9%.
4. the preparation method of rifamycin-S crystal described in any one of claims 1 to 3, comprises the following steps：
A, rifamycin-S is dissolved in tetrahydrofuran；
B, addition acidic alumina are stirred 20~50 minutes, and alumina removed by filtration obtains tetrahydrofuran filtrate；
C, to hexamethylene is added in above-mentioned tetrahydrofuran filtrate, solid is collected by filtration, dry, obtain rifamycin-S crystal.
5. the preparation method of rifamycin-S crystal according to claim 4, it is characterised in that：Tetrahydrofuran described in step a
It is 1~5 ︰ 1 with the envelope-bulk to weight ratio of rifamycin-S.
6. the preparation method of rifamycin-S crystal according to claim 4, it is characterised in that：Acidic oxidation described in step b
Aluminium is 0.01~0.05 ︰ 1 with the weight ratio of rifamycin-S.
7. the preparation method of rifamycin-S crystal according to claim 4, it is characterised in that：Hexamethylene described in step c with
The volume ratio of tetrahydrofuran filtrate is 5~20 ︰ 1.
8. the preparation method of rifamycin-S crystal according to claim 4, it is characterised in that：Hexamethylene is added described in step c
The mode of alkane is dropwise addition.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109358140A (en) * | 2018-10-17 | 2019-02-19 | 上海市食品药品检验所 | A kind of detection method of rifaximin raw material and its formulation components |
| CN110687217A (en) * | 2018-08-07 | 2020-01-14 | 中国科学院大连化学物理研究所 | Method for measuring rifamycin S by liquid chromatography |
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| US3933801A (en) * | 1973-11-29 | 1976-01-20 | Archifar Industrie Chimiche Del Trentino S.P.A. | Process for preparing rifamycin S by hydrolysis of rifamycin O |
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| CN109358140A (en) * | 2018-10-17 | 2019-02-19 | 上海市食品药品检验所 | A kind of detection method of rifaximin raw material and its formulation components |
| CN109358140B (en) * | 2018-10-17 | 2021-07-30 | 上海市食品药品检验研究院 | Rifaximin raw material and detection method of preparation components thereof |
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