CN105017228A - Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor - Google Patents
Ledipasvir intermediate monosulfate, crystalline form thereof and preparation method therefor Download PDFInfo
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- CN105017228A CN105017228A CN201510390769.3A CN201510390769A CN105017228A CN 105017228 A CN105017228 A CN 105017228A CN 201510390769 A CN201510390769 A CN 201510390769A CN 105017228 A CN105017228 A CN 105017228A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- 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
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Abstract
The invention discloses a ledipasvir intermediate monosulfate, a crystalline form thereof and a preparation method therefor, and specifically discloses a compound (crystal-form or amorphous) shown in a formula I, a preparation method therefor and application thereof. According to the preparation method provided by the invention, the crystal form I of the prepared compound shown in the formula I is good in light stability.
Description
Technical field
The present invention relates to medicinal chemistry art, particularly, relate to a kind of Lei Dipawei intermediate monosulfate, its crystal formation and amorphous substance and its production and use.
Background technology
Lei Dipawei (Ledipasvir, LDV) be the third liver medicine that Gilead develops, FDA has authorized LDV/SOF (Sofosbuvir) fixed dosage medicinal composition breakthrough therapy identification, this combination treatment was expected to cure genotype 1HCV patient in the time being as short as 8 weeks, simultaneously without the need to injection of interferon or associating ribavirin (Ribavirin).
The synthetic route of Lei Dipawei is shown below, and wherein, formula II compound is the key intermediate of Lei Dipawei, and the quality of quality to subsequent reactions and Lei Dipawei bulk drug of formula II compound has profound influence.
Wherein the different salt form of compound are the important means improved compound crystal performance, remove impurity, improve the quality of products.Due to molecular structure, the crystallinity of formula II compound own is very poor, and is difficult to salify, at present not about the report of formula II compound salify crystal formation.
Therefore, this area can be used as in the urgent need to exploitation the high purity intermediate producing Lei Dipawei, and especially crystalline solid form, so that the purity and the quality that improve final product (Lei Dipawei).
Summary of the invention
The object of this invention is to provide a kind of the high purity intermediate and the Synthesis and applications thereof that are particularly suitable for producing Lei Dipawei.
First aspect present invention provides a kind of monosulfate of Lei Dipawei midbody compound, has the structure shown in formula I:
In another preference, described formula I is crystal formation or amorphous.
In another preference, purity >=99.0% of described formula I, more preferably >=99.2%.
Second aspect present invention provides a kind of preparation method of formula I, comprises step:
(a) under inert solvent, by the midbody compound of the Lei Dipawei shown in formula II and sulfuric acid reaction, production I:
In another preference, the midbody compound of the Lei Dipawei shown in described formula II and the mol ratio of sulfuric acid are 1:1-1:1.5, are preferably 1:1-1:1.2.
In another preference, described inert solvent is selected from lower group: (i) ethanol, tetrahydrofuran (THF) or its combination; (ii) acetonitrile, acetonitrile/tetrahydrofuran (THF) mixed solvent or its combination.
In another preference, in described step (a), temperature of reaction is 0-50 DEG C, and being preferably 4-35 DEG C, is more preferably 10-25 DEG C.
In another preference, in described step (a), the reaction times is 0.1-24 hour, and being preferably 0.2-12 hour, is more preferably 0.5-3 hour.
In another preference, organize in inert solvent at (i) and react, and crystallization is carried out to the reaction mixture formed, thus the formula I of obtained crystallized form.
In another preference, organize in inert solvent at (ii) and react, and the reaction mixture formed is separated, thus obtained unbodied formula I.
In another preference, described method also comprises step: using described amorphous substance as raw material, for the preparation of formula I crystal formation I.
Third aspect present invention provides a kind of crystal formation of formula I, described crystal formation is crystal formation I, its X-ray powder diffraction pattern comprises the 2 θ values that more than 3 or 3 are selected from lower group: 4.6 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.8 ° ± 0.2 °, 16.2 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.7 ° ± 0.2 °, 21.3 ° ± 0.2 °
In another preference, the X-ray powder diffraction pattern of described crystal formation comprises the 2 θ values of lower group of A1: 4.6 ° ± 0.2 °, 16.2 ° ± 0.2 ° and 21.3 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal formation also comprises the 2 θ values being selected from lower group of A2: 11.6 ° ± 0.2 °, 13.8 ° ± 0.2 ° and 18.7 ° ± 0.2 °.
In another preference, described X-ray powder diffraction pattern is measure under following condition: Cu-Ka,
In another preference, the X-ray powder diffraction pattern of described crystal formation substantially as Fig. 1 characterize.
In another preference, described crystal formation has the one or more features being selected from lower group:
I starting temperature (onset) that () its dsc analyzes collection of illustrative plates is 169.81 ± 3 DEG C, and peak temperature (peak) is 182.26 ± 3 DEG C; More preferably, its dsc analyze collection of illustrative plates substantially as Fig. 2 characterize;
(ii) its thermogravimetric analysis collection of illustrative plates substantially as Fig. 3 characterize.
Fourth aspect present invention provides the preparation method of the crystal formation of the formula I described in a kind of third aspect present invention, and described preparation method comprises the steps:
(a) under inert solvent, by the midbody compound of the Lei Dipawei shown in formula II and sulfuric acid reaction, production I:
B () carries out crystallization treatment to the formula I that step (a) generates, thus form the crystal formation described in third aspect present invention.
In another preference, described method comprises the one or more features being selected from lower group:
In step (b), under room temperature (as 4-30 DEG C), the solution or suspension (or reaction mixture of step (a)) that contain formula I are placed 1-72 hour (preferably 5-36 hour), then carry out centrifuging, thus obtain the crystal formation of described formula I.
Fifth aspect present invention provides the purposes of the formula I described in a kind of first aspect present invention, for the preparation of the medicine for the treatment of third liver.
In another preference, described medicine comprises: Lei Dipawei.
In another preference, described formula I is crystal formation or amorphous.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffractogram (XRPD) of formula I crystal formation I.
Fig. 2 shows the differential scanning calorimetric analysis spectrogram (DSC) of formula I crystal formation I.
Fig. 3 shows the thermogravimetic analysis (TGA) spectrogram (TGA) of formula I crystal formation I.
Wherein, in above-mentioned each figure, onset represents initially (initial value), and peak represents peak (peak value).
Embodiment
The present inventor, through extensive and deep research, has carried out a large amount of optimizing research to the preparation technology of Lei Dipawei, unexpectedly obtains a kind of high purity intermediate being particularly suitable for producing Lei Dipawei first.Described intermediate is formula I (comprising its crystal formation and amorphous substance).The crystal formation of formula I of the present invention is not only easy to preparation, and with the light stability that the formula II compound tool of salt-independent shape is significantly improved, therefore contribute to reducing impurity, and then improve the quality of final product Lei Dipawei.Contriver completes the present invention on this basis.
Term
Intermediate and crystal formation thereof
As used herein, term " intermediate of the present invention " refers to formula I, comprises that it is amorphous, crystal formation or its mixture.
As used herein, between described " crystal of the present invention ", " crystal formation of the present invention ", " crystal formation of formula I of the present invention ", " crystal formation of formula I ", " formula I crystal formation ", be used interchangeably, all refer to the crystal formation I of formula I.
As used herein, the structure of described formula I is as follows:
In another preference, described formula I is crystal formation or amorphous.
In another preference, purity >=99.0% of described formula I, more preferably >=99.2%.
Further, described formula I is obtained by following method:
(a) under inert solvent, by the midbody compound of the Lei Dipawei shown in formula II and sulfuric acid reaction, production I:
In another preference, the midbody compound of the Lei Dipawei shown in described formula II and the mol ratio of sulfuric acid are 1:1-1:1.5, are preferably 1:1-1:1.2.
In another preference, described inert solvent is selected from lower group: (i) ethanol, tetrahydrofuran (THF) or its combination; (ii) acetonitrile, acetonitrile/tetrahydrofuran (THF) mixed solvent or its combination.
In another preference, in described step (a), temperature of reaction is 0-50 DEG C, and being preferably 4-35 DEG C, is more preferably 10-25 DEG C.
In another preference, in described step (a), the reaction times is 0.1-24 hour, and being preferably 0.2-12 hour, is more preferably 0.5-3 hour.
In another preference, organize in inert solvent at (i) and react, and crystallization is carried out to the reaction mixture formed, thus the formula I of obtained crystallized form.
In another preference, organize in inert solvent at (ii) and react, and the reaction mixture formed is separated, thus obtained unbodied formula I.
In another preference, described method also comprises step: using described amorphous substance as raw material, for the preparation of formula I crystal formation I.
And, as used herein, the crystal formation of described formula I is crystal formation I, specific features is as follows: its X-ray powder diffraction pattern comprises the 2 θ values that more than 3 or 3 are selected from lower group: 4.6 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.8 ° ± 0.2 °, 16.2 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.7 ° ± 0.2 °, 21.3 ° ± 0.2 °
In another preference, the X-ray powder diffraction pattern of described crystal formation comprises the 2 θ values of lower group of A1: 4.6 ° ± 0.2 °, 16.2 ° ± 0.2 ° and 21.3 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal formation also comprises the 2 θ values being selected from lower group of A2: 11.6 ° ± 0.2 °, 13.8 ° ± 0.2 ° and 18.7 ° ± 0.2 °.
In another preference, described X-ray powder diffraction pattern is measure under following condition: Cu-Ka,
In another preference, the X-ray powder diffraction pattern of described crystal formation substantially as Fig. 1 characterize.
In another preference, described crystal formation has the one or more features being selected from lower group:
I starting temperature (onset) that () its dsc analyzes collection of illustrative plates is 169.81 ± 3 DEG C, and peak temperature (peak) is 182.26 ± 3 DEG C; More preferably, its dsc analyze collection of illustrative plates substantially as Fig. 2 characterize;
(ii) its thermogravimetric analysis collection of illustrative plates substantially as Fig. 3 characterize.
Preparation method
The invention provides a kind of preparation method of formula I, comprise the formula I preparing amorphous and crystalline forms.
Because crystal formation has higher purity (as >=99%), therefore preferably prepare crystal formation in the present invention, and this crystal formation is used as the raw material of Lei Dipawei.
A kind of mode preparing crystal formation first prepares unbodied formula I, such as those skilled in the art can prepare the amorphous substance of formula I with reference to instruction of the present invention, then this amorphous substance is used as the raw material of preparation I compound crystal formation, thus obtained crystallized product, as crystal formation I.
The method that another kind prepares crystal formation is reacted at formula II compound and moderate amount of sulfuric acid, among reaction or directly form the formula I of crystalline form afterwards.
In a preference, the method for preparation I compound crystal formation of the present invention comprises step:
I (), under inert solvent (as ethanol, tetrahydrofuran (THF) or its combination), by formula II compound and sulfuric acid reaction, generates the reaction mixture containing formula I;
(ii) optionally described reaction mixture is placed for some time (as placed 1-72 hour, preferably 5-36 hour); And/or optionally in described reaction mixture, add crystal seed;
(iii) described reaction mixture is separated (as centrifuging), thus obtains the crystal formation of described formula I.
Crystallization
In the present invention, can working solution be passed through, the solubility limit of compound of interest is exceeded, thus complete production-scale crystallization.This can have been come by multiple method, and such as, dissolved compound at relatively high temperature, then below cooling solution to saturation limit.Or reduce liquid volume by boiling, atmospheric evaporation, vacuum-drying or the certain methods by other.By adding solvent resistant or compound has the solvent of low solubleness or the mixture of such solvent wherein, reduce the solubleness of compound of interest.Another kind of optional method is that adjust ph is to reduce solubleness.About the detailed description of crystallization aspect refers to Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If expect that the formation of salt and crystallization occur simultaneously, if salt is less than material dissolution degree in reaction medium, so add the direct crystallization that suitable acid or alkali can cause required salt.Equally, in the medium that the form finally wanted is less than reactants dissolved degree, completing of building-up reactions can make final product direct crystallization.
The optimization of crystallization can comprise and being inoculated in crystallization medium as crystal seed with the crystal of desired form.In addition, many crystallization method use the combination of above-mentioned strategy.An embodiment is at high temperature by interested compound dissolution in a solvent, is added the solvent resistant of proper volume subsequently, to make system just in time under saturated level by controlled way.Now, the crystal seed (and keeping the integrity of crystal seed) of desired form can be added, by system cooling to complete crystallization.
Major advantage of the present invention comprises:
(1) with formula II Compound Phase ratio, the light stability that the crystal formation I tool of formula I of the present invention is significantly improved.
(2) preparation method of formula I of the present invention (crystal formation or amorphous substance) is simple, quick, is convenient to large-scale production.
(3) solubleness of formula I of the present invention in some solvent is low especially, and therefore form precipitation or crystallization at short notice, therefore purification and separation is very convenient and quick.
(4) crystal formation I of the present invention has very high purity (as >=99%), is especially suitable for use as the intermediate producing Lei Dipawei, thus improves the quality of end product Lei Dipawei, and reduces impurity.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Raw material, instrument and universal method
Raw material: formula II compound (being prepared see the method in US8088368).
Chromatography of ions: Dionex ICS2100, moving phase: 30mM NaOH, detector: ECD, column temperature: 35 DEG C, flow velocity: 1.0ml/min, suppressor: ASRS 4mm, Dionex IonPac AS18 (250 × 4mm) separator column.
XRPD:Bruker D8Advance X-ray powder diffractometer, Cu target, Ka wavelength, tube voltage 40KV, tube current 40mA.Sweep limit: 3-40 ° 2-Theta; Stepping: 0.02 °; Sweep velocity: 1 step/second.
DSC:PE DSC8500 differential scanning calorimeter; Temperature range: 50-250 DEG C; Heating rate: 10 DEG C/min.
TGA:NETZSCH TG 209F3 thermogravimetric analyzer; Temperature range: 30-400 DEG C; Heating rate: 10 DEG C/min.
The preparation (amorphous substance) of embodiment 1 formula I
Take 37mg formula II compound to 1.5ml centrifuge tube, add the THF of 0.1mL, ultrasonic extremely dissolving, add the acetonitrile solution of 0.1mL0.5M sulfuric acid, adularescent solid precipitation is formed at once.
Get partial white solid precipitation, through polarizing microscope qualification, confirm as amorphous forms.
The preparation (crystal formation I) of embodiment 2 formula I
(1) take 37mg formula II compound to 1.5ml centrifuge tube, add 0.1mL ethanol.Ultrasonic to dissolving.Add the ethanolic soln of 0.1mL 0.5M sulfuric acid.This reaction mixture is at room temperature placed 6 hours, has solid precipitation to separate out.Get fraction solids precipitation, through polarizing microscope qualification, confirm as crystal.
(2) whizzer will be placed in containing described centrifuge tube, and leave the heart 5 minutes 12000, remove supernatant liquor, by the solid that is separated under room temperature dry 1 hour.
(3) dried solid is tested sulfate radical content by chromatography of ions, carried out the sign of solid form by XRPD, DSC and TGA etc.
Result
(1) ion chromatography result shows, in this crystal, in sulfate radical content formula I, sulfate radical theoretical content (11.0wt%) is substantially identical.In addition, in conjunction with the mol ratio (1:1) of sulfuric acid in salification process and formula II compound, this crystal is pointed out to be monosulfate.
(2) XRPD collection of illustrative plates
The crystal formation of formula I is named as crystal formation I, and its XRPD collection of illustrative plates as shown in Figure 1.Main diffraction peak and relative intensity as shown in table 1.
The XRPD data of this crystal of table 1
| 2θ(°) | Relative intensity (%) |
| 4.6 | 100.0 |
| 11.6 | 27.3 |
| 13.8 | 26.3 |
| 16.2 | 35.8 |
| 17.1 | 20.7 |
| 18.7 | 31.1 |
| 21.3 | 50.8 |
(3) dsc analysis result
The dsc analysis result of the crystal formation I of formula I as shown in Figure 2.Result shows, between 50-220 DEG C, the heat flow curve of the crystal formation of formula I has an endotherm(ic)peak, and its starting temperature is 169.81 DEG C, and peak temperature (peak) is 182.26 DEG C.
(4) TGA analytical results
The TGA analytical results of the crystal formation I of formula I as shown in Figure 3.Result shows, between 130-220 DEG C, the thermogravimetric curve of crystal has the weightless step (compound decomposition) of obvious 21.01%.
(5) purity check
HPLC analyzes and shows, after generating the crystal formation I of monosulfate from the reaction of formula II compound, HPLC purity brings up to >=99.2% (formula I) from 91.6% (formula II compound).This result shows, significantly can remove impurity after becoming salt-pepper noise, therefore contributes to the quality improving end product Lei Dipawei.
The crystallization of embodiment 3 formula I amorphous substance
Take 100mg formula I (method for making is with embodiment 1) to 1.5ml centrifuge tube, add 0.2mL ethanol and form suspension, add about 5mg formula I crystal formation I (embodiment 2).
This suspension being placed in room temperature keeps battle array to shake 3 days, and confirm through polarizing microscope, in suspension, solid is converted into crystal from unformed, and further XRPD identifies and confirms that this crystal is crystal formation I.
Embodiment 4 light durability is assessed
In the present embodiment, formula I crystal formation I (embodiment 2) and the light durability of formula II compound are investigated.Method is as follows:
Testing sample is placed in watch-glass, spreads out into the thin layer that thickness is no more than 1mm, being positioned over intensity of illumination is in the exposure experiments to light case of 4400Lux, and continue illumination in 12 days, total illumination is 1.2M lux hour.Then, by HPLC method, the sample purity through photo-irradiation treatment is checked, and contrast with initial purity.
Result shows, the light durability of the crystal formation I of formula I is significantly increased (table 2) compared to formula II compound.
Table 2 stability result
The screening of all kinds of salt of embodiment 5 formula II compound
Take 37mg formula II compound to a series of 1.5ml centrifuge tube, add 0.1mL ethanol respectively, ultrasonic to dissolving.The ethanol of the different acid of preparation or acetonitrile solution (see table 3).
The acid solution of equimolar ratio is dripped in formula II compound solution.If there is precipitation to generate, confirm whether precipitation is crystal by polarizing microscope.If formation settled solution, be then uncoveredly placed in the slow solvent flashing of room temperature.
The screening of table 3 formula II compound salt
| Acid | Phenomenon | Result |
| Hydrochloric acid | Solid precipitation is separated out | Unformed |
| Sulfuric acid | Solid precipitation is separated out | Monosulfate |
| Phosphoric acid | Oily matter is separated out | Unformed |
| Oxalic acid | Solid precipitation is separated out | Unformed |
| Methylsulfonic acid | Solid precipitation is separated out | Unformed |
| Tosic acid | Solid precipitation is separated out | Unformed |
In addition, formula I is carried out to the test subsequent step of Lei Dipawei (preparation) of Deprotection (boc), result shows, in formula I, the existence of sulfate radical for this follow-up deprotection reaction without any disadvantageous effect.
Comprehensive the above results shows, the crystal formation of formula I (i.e. the monosulfate of formula II compound) is especially suitable for use as the intermediate of preparation Lei Dipawei.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the monosulfate of Yi Zhong Lei Dipawei midbody compound, is characterized in that, has the structure shown in formula I:
2. a preparation method for formula I, is characterized in that, comprises step:
(a) under inert solvent, by the midbody compound of the Lei Dipawei shown in formula II and sulfuric acid reaction, production I:
3. method as claimed in claim 2, it is characterized in that, the midbody compound of the Lei Dipawei shown in described formula II and the mol ratio of sulfuric acid are 1:1-1:1.5, are preferably 1:1-1:1.2.
4. method as claimed in claim 2, it is characterized in that, described method also comprises step: using described amorphous substance as raw material, for the preparation of formula I crystal formation I.
5. the crystal formation of a formula I, it is characterized in that, described crystal formation is crystal formation I, its X-ray powder diffraction pattern comprises the 2 θ values that more than 3 or 3 are selected from lower group: 4.6 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.8 ° ± 0.2 °, 16.2 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.7 ° ± 0.2 °, 21.3 ° ± 0.2 °
6. crystal formation as claimed in claim 5, it is characterized in that, the X-ray powder diffraction pattern of described crystal formation comprises the 2 θ values of lower group of A1: 4.6 ° ± 0.2 °, 16.2 ° ± 0.2 ° and 21.3 ° ± 0.2 °.
7. crystal formation as claimed in claim 5, it is characterized in that, the X-ray powder diffraction pattern of described crystal formation also comprises the 2 θ values being selected from lower group of A2: 11.6 ° ± 0.2 °, 13.8 ° ± 0.2 ° and 18.7 ° ± 0.2 °.
8. crystal formation as claimed in claim 5, it is characterized in that, described crystal formation has the one or more features being selected from lower group:
I starting temperature (onset) that () its dsc analyzes collection of illustrative plates is 169.81 ± 3 DEG C, and peak temperature (peak) is 182.26 ± 3 DEG C; More preferably, its dsc analyze collection of illustrative plates substantially as Fig. 2 characterize;
(ii) its thermogravimetric analysis collection of illustrative plates substantially as Fig. 3 characterize.
9. a preparation method for the crystal formation of formula I according to claim 5, is characterized in that, described preparation method comprises the steps:
(a) under inert solvent, by the midbody compound of the Lei Dipawei shown in formula II and sulfuric acid reaction, production I:
B () carries out crystallization treatment to the formula I that step (a) generates, thus form crystal formation according to claim 3.
10. a purposes for formula I according to claim 1, is characterized in that, for the preparation of the medicine for the treatment of third liver.
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Cited By (1)
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| CN106932503A (en) * | 2015-12-31 | 2017-07-07 | 江苏正济药业股份有限公司 | A kind of analysis method of measure Lei Dipawei purity |
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| CN102596936A (en) * | 2009-05-13 | 2012-07-18 | 吉里德科学公司 | Antiviral compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106932503A (en) * | 2015-12-31 | 2017-07-07 | 江苏正济药业股份有限公司 | A kind of analysis method of measure Lei Dipawei purity |
| CN106932503B (en) * | 2015-12-31 | 2019-08-27 | 江苏正济药业股份有限公司 | A kind of analysis method measuring Lei Dipawei purity |
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Application publication date: 20151104 |