CN112898288A - Method for preparing crystal form 3 of raltegravir potassium - Google Patents
Method for preparing crystal form 3 of raltegravir potassium Download PDFInfo
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- CN112898288A CN112898288A CN201911223910.5A CN201911223910A CN112898288A CN 112898288 A CN112898288 A CN 112898288A CN 201911223910 A CN201911223910 A CN 201911223910A CN 112898288 A CN112898288 A CN 112898288A
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- ethyl alcohol
- absolute ethyl
- potassium
- potassium hydroxide
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- 239000013078 crystal Substances 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 11
- MGWQOOSAUWCOOU-UHFFFAOYSA-N 1-(3-fluorophenyl)pyrrole-2-carbaldehyde Chemical compound FC1=CC=CC(N2C(=CC=C2)C=O)=C1 MGWQOOSAUWCOOU-UHFFFAOYSA-N 0.000 title abstract description 20
- 229960003490 raltegravir potassium Drugs 0.000 title abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 55
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000012535 impurity Substances 0.000 claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 238000000967 suction filtration Methods 0.000 claims abstract description 11
- 235000019441 ethanol Nutrition 0.000 claims abstract description 10
- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- 230000015556 catabolic process Effects 0.000 abstract description 4
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000843 powder Substances 0.000 abstract description 3
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 2
- 229960004742 raltegravir Drugs 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 238000000634 powder X-ray diffraction Methods 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 230000006641 stabilisation Effects 0.000 description 8
- 238000011105 stabilization Methods 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- SHOJXDKTYKFBRD-UHFFFAOYSA-N 4-Methyl-3-penten-2-one, 9CI Chemical compound CC(C)=CC(C)=O SHOJXDKTYKFBRD-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical group [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- MJNIWUJSIGSWKK-UHFFFAOYSA-N Riboflavine 2',3',4',5'-tetrabutanoate Chemical compound CCCC(=O)OCC(OC(=O)CCC)C(OC(=O)CCC)C(OC(=O)CCC)CN1C2=CC(C)=C(C)C=C2N=C2C1=NC(=O)NC2=O MJNIWUJSIGSWKK-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 229940111682 isentress Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- NLDVPINGTPMESH-UHFFFAOYSA-N n-[2-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]propan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide;potassium Chemical group [K].O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C NLDVPINGTPMESH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a crystal form 3 of raltegravir potassium, which comprises the following steps of (1) suspending raltegravir in absolute ethyl alcohol, and controlling the temperature of a system to be below 10 ℃; (2) preparing an absolute ethyl alcohol solution of potassium hydroxide, and dissolving the absolute ethyl alcohol solution clearly for later use; (3) dropwise adding the potassium hydroxide ethanol solution prepared in the step 2 into the Latiravi ethanol suspension, quickly heating the reaction system to 20-30 ℃ after dropwise adding, and keeping the temperature and stirring; (4) and carrying out suction filtration and drying to obtain the solid of the crystal form 3 of the raltegravir potassium. The method is stable and simple to operate, and the product quality meets the quality standard requirements of the bulk drugs; the risk that gene toxic impurities are possibly generated in the original process is avoided; through the accurate control of reaction temperature, reduce the production of degradation impurity, can fine realization powder granularity's control moreover, avoid the production of mixed crystal, reduce the suction filtration degree of difficulty simultaneously, be convenient for the industrialization implementation.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a crystal form 3 of raltegravir potassium.
Background
The chemical name of the Raltegravir Potassium is N- (2- (4- (4-fluorobenzylcarbamoyl) -5-hydroxy-1-methyl-6-oxo-1, 6-dihydropyrimidin-2-yl) propan-2-yl) -5-methyl-1, 3, 4-oxadiazole-2-carboxamide Potassium salt, the trade name of which is Isentress, developed by Merck company in America, approved by FDA on the market at 10 months of 2007, and is the first HIV integrase inhibitor applied to clinic in the world and used for treating acquired immunodeficiency syndrome (HIV).
Latirasvir compounds are disclosed in patent WO03035077 and methods for their synthesis are disclosed.
Patent WO 200606060730 discloses crystal form 1, crystal form 2 and crystal form 3 of blatiramer potassium. Wherein, the crystal form 1 is an anhydrate, the X-ray powder diffraction shows that the 2 theta value has characteristic peaks at 5.9 degrees, 12.5 degrees, 20.0 degrees, 20.6 degrees and 25.6 degrees, and the differential scanning calorimetry curve shows that the crystal form has an endothermic peak at 279 ℃; the crystal form 2 is a hydrated crystal sylvite form, the X-ray powder diffraction shows that the 2 theta value has characteristic peaks at 7.9 degrees, 13.8 degrees, 15.7 degrees, 24.5 degrees and 31.5 degrees, and the differential scanning calorimetry curve shows that the crystal form has two wide endothermic peaks at 146 ℃, 239 ℃ and a sharp absorption peak at 276 ℃; the crystal form 3 is also an anhydrate form of the potassium raltegravir, the 2 theta values of the crystal form 3 have characteristic peaks at 7.4 degrees, 7.8 degrees, 12.3 degrees, 21.6 degrees and 64.7 degrees as shown by X-ray powder diffraction, and a differential scanning calorimetry curve shows that the crystal form has a single endothermic peak at 284 ℃.
The preparation of the crystal form 3 in the patent requires that amorphous potassium salt is obtained firstly at-78 ℃, and then the amorphous potassium salt is crystallized in an ethanol solvent. The reaction conditions are harsh, the operation is complex, and industrialization is not easy to realize.
Patent WO2017001996 reports a preparation method of a crystal form 3 of raltegravir potassium, which is implemented according to the patent method, and the degradation impurity E (structure shown below) in the obtained raltegravir potassium product exceeds the product quality limit, and is not easy to refine, and the obtained product is a small amount of mixed crystal containing a crystal form 1.
Patent WO2018051239 also reports a process for the preparation of crystalline form 3 of raltegravir potassium, in which a ketone solvent is used. As is known, the reaction of ketone solvent under alkaline condition can easily produce isopropylidene acetone impurity, which is genotoxic impurity and is difficult to control in product limit.
The crystal form 1 and the crystal form 3 of the latrevir potassium are both anhydrous crystal forms, and the experimental data of the patent WO2018051239 show that the crystal form 3 has good chemical stability and crystal form stability, and meanwhile, the solubility experiment shows that the crystal form 3 has better water solubility than the crystal form 1, so that the crystal form 3 is a good choice for developing a latrevir potassium preparation. Therefore, the preparation process of the crystal form 3, which is stable in development and simple in operation, has the product quality meeting the quality standard requirements of the bulk drugs and can be industrially implemented, can provide more choices for the development of the preparation form of the lattiravir potassium and meets the market demand of the product.
Disclosure of Invention
The existing preparation method of the crystal form 3 of the raltegravir potassium is harsh in reaction conditions, difficult to implement in production process, or easy to generate degradation impurities, and the product quality can not meet the requirements, or the generation of genotoxic impurities is increased, and the product is difficult to control, so that a new preparation method of the crystal form 3 is urgently needed to be developed to meet the requirements of the existing market on the development of various preparation forms of the raltegravir potassium.
The invention provides a novel preparation method of a crystal form 3 of the raltegravir potassium, which is stable, simple to operate, capable of meeting the quality standard requirements of raw material medicines and capable of being industrially implemented.
One aspect of the invention provides a novel preparation method of a crystal form 3 of raloxivir potassium, which is characterized by comprising the following steps
(1) Suspending Latelavir in absolute ethyl alcohol, and controlling the temperature of the system to be below 10 ℃;
(2) preparing an absolute ethyl alcohol solution of potassium hydroxide, and dissolving the absolute ethyl alcohol solution clearly for later use;
(3) dropwise adding the potassium hydroxide ethanol solution prepared in the step 2 into the Latiravi ethanol suspension, heating the reaction system to 20-30 ℃ after dropwise adding, and keeping the temperature and stirring;
(4) and carrying out suction filtration and drying to obtain the solid of the crystal form 3 of the raltegravir potassium.
Wherein the purity of the solid obtained in the step 4 is not lower than 99.6 percent, and the purity of a single impurity is not higher than 0.10 percent.
In another preferred example, the molar ratio of the potassium hydroxide to the latifoliate viras in the step (2) is 0.95-1.05: 1.
The invention has the advantages that: the novel preparation method of the crystal form 3 of the raltegravir potassium is provided, the preparation method is simple to operate, and the production conditions are easy to control; the risk that gene toxic impurities are possibly generated in the original process is avoided; through the accurate control of reaction temperature, reduce the production of degradation impurity, can fine realization powder granularity's control moreover, avoid the production of mixed crystal, reduce the suction filtration degree of difficulty simultaneously, be convenient for the industrialization implementation.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. For reasons of brevity and description are not repeated herein.
Drawings
Figure 1 shows an X-ray powder diffraction pattern (XRPD) of crystalline form 3 of raltegravir potassium;
figure 2 shows a Differential Scanning Calorimetry (DSC) spectrum of crystalline form 3 of raltegravir potassium.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
X-ray powder diffraction (XRPD):
x-ray powder diffraction instrument: brucker D8 advance X-ray powder diffractometer; the parameters of the X-ray powder diffraction are as follows: copper target
Scanning was performed at room temperature.
Voltage: 40 kilovolt (kv)
Current: 40 milliampere (mA)
Scanning mode: continuous
Scanning range: 2.0 to 50.0 DEG C
Step length: 0.020 °
The measurement time per step is 0.1 second
Differential Scanning Calorimetry (DSC):
differential Scanning Calorimetry (DSC) instrument: type TA Q2000.
Differential Scanning Calorimetry (DSC) analysis method parameters were as follows:
temperature range: 25 to 250 DEG C
Scanning speed: 10 ℃/min
Protective gas: nitrogen, 50 ml/min
Example 1
331.5g of potassium hydroxide and 12L of absolute ethyl alcohol are added into a reaction bottle, and the mixture is mechanically stirred and dissolved in a clear solution under the argon environment for later use.
2.5kg of Laticaravir free acid and 12.5L of absolute ethyl alcohol are added into a 30L reaction kettle and stirred, and the temperature of the system is controlled to be not higher than 10 ℃.
Dropwise adding the prepared potassium hydroxide ethanol solution into an ethanol solution of the Laticagrev free acid, and after dropwise adding, heating the reaction system to 20-25 ℃. Stirring for 1-2 hours under heat preservation, performing suction filtration, washing a filter cake for 1-2 times by using absolute ethyl alcohol, drying the obtained wet product at 40-45 ℃ under reduced pressure to constant weight to obtain a solid in a crystal form 3 of the raltegravir potassium, wherein an XRD spectrogram is shown in figure 1, and a DSC spectrogram is shown in figure 2 (the weight yield is 103.1%, and the purity is 99.8%).
Example 2
331.5g of potassium hydroxide and 12L of absolute ethyl alcohol are added into a reaction bottle, and the mixture is mechanically stirred and dissolved in a clear solution under the argon environment for later use.
2.5kg of Laticaravir free acid and 12.5L of absolute ethyl alcohol are added into a 30L reaction kettle and stirred, and the temperature of the system is controlled to be not higher than 10 ℃.
Dropwise adding the prepared potassium hydroxide ethanol solution into an ethanol solution of the Laticagrev free acid, and after dropwise adding, heating the reaction system to 20-25 ℃. Stirring for 1-2 hours under heat preservation, performing suction filtration, washing a filter cake for 1-2 times by using absolute ethyl alcohol, drying the obtained wet product at 40-45 ℃ under reduced pressure to constant weight to obtain a solid in a crystal form 3 of the raltegravir potassium, wherein an XRD spectrogram is shown in figure 1, and a DSC spectrogram is shown in figure 2 (the weight yield is 100.3%, and the purity is 99.7%).
Example 3
337.6g of potassium hydroxide and 12L of absolute ethyl alcohol are added into a reaction bottle, and the mixture is mechanically stirred and dissolved in a clear solution under the argon environment for standby.
2.5kg of Laticaravir free acid and 12.5L of absolute ethyl alcohol are added into a 30L reaction kettle and stirred, and the temperature of the system is controlled to be not higher than 10 ℃.
Dropwise adding the prepared potassium hydroxide ethanol solution into an ethanol solution of the Laticagrev free acid, and after dropwise adding, heating the reaction system to 20-25 ℃. Stirring for 1-2 hours under heat preservation, performing suction filtration, washing a filter cake for 1-2 times by using absolute ethyl alcohol, drying the obtained wet product at 40-45 ℃ under reduced pressure to constant weight to obtain a solid in a crystal form 3 of the raltegravir potassium, wherein an XRD spectrogram is shown in figure 1, and a DSC spectrogram is shown in figure 2 (the weight yield is 104.5%, and the purity is 99.8%).
Example 4
337.6g of potassium hydroxide and 12L of absolute ethyl alcohol are added into a reaction bottle, and the mixture is mechanically stirred and dissolved in a clear solution under the argon environment for standby.
2.5kg of Laticaravir free acid and 12.5L of absolute ethyl alcohol are added into a 30L reaction kettle and stirred, and the temperature of the system is controlled to be not higher than 10 ℃.
Dropwise adding the prepared potassium hydroxide ethanol solution into an ethanol solution of the Laticagrev free acid, and after dropwise adding, heating the reaction system to 20-25 ℃. Stirring for 1-2 hours under heat preservation, performing suction filtration, washing a filter cake for 1-2 times by using absolute ethyl alcohol, drying the obtained wet product at 40-45 ℃ under reduced pressure to constant weight to obtain a solid in a crystal form 3 of the raltegravir potassium, wherein an XRD spectrogram is shown in figure 1, and a DSC spectrogram is shown in figure 2 (the weight yield is 103.5%, and the purity is 99.6%).
Comparative example 1
331.5g of potassium hydroxide and 12L of absolute ethyl alcohol are added into a reaction bottle, and the mixture is mechanically stirred and dissolved in a clear solution under the argon environment for later use.
Adding 2.5kg of Laticaravir free acid and 12.5L of absolute ethyl alcohol into a 30L reaction kettle, stirring, and controlling the system temperature to be 15-20 ℃.
And dropwise adding the prepared potassium hydroxide ethanol solution into an ethanol solution of the Laticagrev free acid, and after dropwise adding, quickly heating the reaction system to 20-25 ℃. Stirring for 1-2 hours under heat preservation, performing suction filtration, wherein the suction filtration speed is low, and the filter cake is viscous.
Comparative example 2
331.5g of potassium hydroxide and 12L of absolute ethyl alcohol are added into a reaction bottle, and the mixture is mechanically stirred and dissolved in a clear solution under the argon environment for later use.
Adding 2.5kg of Laticaravir free acid and 12.5L of absolute ethyl alcohol into a 30L reaction kettle, stirring, and controlling the system temperature to be 20-25 ℃.
And (3) dropwise adding the prepared potassium hydroxide ethanol solution into an ethanol solution of the Laticagrev free acid, and after dropwise adding, keeping the temperature and stirring for 1-2 hours, wherein the obtained product is not filtered, thick crystal slurry and difficult to pump and filter.
The experimental result of the influencing factors of the crystal form 3 of the Latiravir obtained by the preparation method of the invention is as follows:
(1) the placing conditions are as follows: 40 ℃ and 75 +/-5% RH
| Time of standing | Chemical purity | Condition of impurities | Stability of crystal form | |
| 0M | 99.807％ | Less than or equal to 0.10 percent of | Form | 3 |
| 1M | 99.767％ | Less than or equal to 0.10 percent of single impurity | Stabilization | |
| 2M | 99.669％ | Less than or equal to 0.10 percent of single impurity | Stabilization | |
| 3M | 99.76％ | Less than or equal to 0.10 percent of single impurity | Stabilization | |
| 6M | 99.7489％ | Less than or equal to 0.10 percent of single impurity | Stabilization |
(2) The placing conditions are as follows: 25 ℃ and 60. + -. 5% RH
| Time of standing | Chemical purity | Condition of impurities | Stability of crystal form | |
| 0M | 99.9067％ | Less than or equal to 0.10 percent of | Form | 3 |
| 3M | 99.9645％ | Less than or equal to 0.10 percent of single impurity | Stabilization | |
| 6M | 99.7274％ | Less than or equal to 0.10 percent of single impurity | Stabilization | |
| 15M | 99.6623％ | Less than or equal to 0.10 percent of single impurity | Stabilization | |
| 18M | 99.3821％ | Less than or equal to 0.10 percent of single impurity | Stabilization |
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (2)
1. A process for preparing crystalline form 3 of raloxivir potassium, characterized in that it comprises the following steps
(1) Suspending Latelavir in absolute ethyl alcohol, and controlling the temperature of the system to be below 10 ℃;
(2) preparing an absolute ethyl alcohol solution of potassium hydroxide, and dissolving the absolute ethyl alcohol solution clearly for later use;
(3) dropwise adding the potassium hydroxide ethanol solution prepared in the step 2 into the Latiravi ethanol suspension, heating the reaction system to 20-30 ℃ after dropwise adding, and keeping the temperature and stirring;
(4) carrying out suction filtration and drying to obtain a solid in a crystal form 3 of the latrevir potassium;
wherein, the purity of the solid obtained in the step 4 is not lower than 99.6 percent, and the purity of a single impurity is not higher than 0.10 percent.
2. The method according to claim 1, wherein the molar ratio of the potassium hydroxide to the latifolir is 0.95-1.05: 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN2013CH05282A (en) * | 2013-11-18 | 2015-08-28 | Reddy’S Lab Ltd Dr | |
| IN2012DN03346A (en) * | 2009-09-18 | 2015-10-23 | Univ Akron | |
| WO2017001996A1 (en) * | 2015-06-29 | 2017-01-05 | Laurus Labs Private Limited | A process for preparing raltegravir potassium form 3 |
| US20190248773A1 (en) * | 2016-09-15 | 2019-08-15 | Lupin Limited | Process for the preparation of pure and stable crystalline raltegravir potassium form 3 |
-
2019
- 2019-12-04 CN CN201911223910.5A patent/CN112898288A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN2012DN03346A (en) * | 2009-09-18 | 2015-10-23 | Univ Akron | |
| IN2013CH05282A (en) * | 2013-11-18 | 2015-08-28 | Reddy’S Lab Ltd Dr | |
| WO2017001996A1 (en) * | 2015-06-29 | 2017-01-05 | Laurus Labs Private Limited | A process for preparing raltegravir potassium form 3 |
| US20190248773A1 (en) * | 2016-09-15 | 2019-08-15 | Lupin Limited | Process for the preparation of pure and stable crystalline raltegravir potassium form 3 |
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