CN106432197A - Ledipasvir midbody monomer tosilate and crystal form and preparation method thereof - Google Patents
Ledipasvir midbody monomer tosilate and crystal form and preparation method thereof Download PDFInfo
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- CN106432197A CN106432197A CN201610808216.XA CN201610808216A CN106432197A CN 106432197 A CN106432197 A CN 106432197A CN 201610808216 A CN201610808216 A CN 201610808216A CN 106432197 A CN106432197 A CN 106432197A
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- 239000013078 crystal Substances 0.000 title claims abstract description 88
- 229950004288 tosilate Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- VRTWBAAJJOHBQU-KMWAZVGDSA-N ledipasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=C3C(F)(F)C4=CC(=CC=C4C3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N([C@@H]3CC[C@H]2C3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21CC2 VRTWBAAJJOHBQU-KMWAZVGDSA-N 0.000 title abstract description 5
- 229960002461 ledipasvir Drugs 0.000 title abstract description 5
- 239000000178 monomer Substances 0.000 title abstract 2
- 239000000126 substance Substances 0.000 claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 67
- 150000001875 compounds Chemical class 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 238000002411 thermogravimetry Methods 0.000 claims description 4
- 208000005176 Hepatitis C Diseases 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 5
- 239000012467 final product Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 17
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000004519 grease Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 229960002063 sofosbuvir Drugs 0.000 description 2
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- 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
- C07D403/02—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 two hetero rings
- C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a ledipasvir midbody monomer tosilate and a crystal form and a preparation method thereof. The crystal form A obtained through the preparation method has the good chemical purity and product quality, and the preparation method is simple and rapid and promotes large-scale production. Meanwhile, the crystal form A has the quite high purity and is particularly suitable for being adopted as a midbody for producing ledipasvir, so that the quality of the final product ledipasvir is improved, and impurities are reduced.
Description
Technical field
The invention belongs to medicinal chemistry art, specifically, the present invention relates to a kind of single pair of first of Lei Dipawei intermediate
Benzene sulfonate, its crystal formation and amorphous substance, and its production and use.
Background technology
Lei Dipawei (Ledipasvir, LDV) is the hepatitis medicine of Gilead exploitation, and FDA has authorized LDV/SOF
(Sofosbuvir) fixed dosage composition of medicine breaks through sex therapy identification, and this combination treatment is expected to be as short as in the time of 8 weeks controlling
More genotype 1HCV patient, simultaneously without injection of interferon or joint Ribavirin (Ribavirin).
Chinese patent application (CN2015101179973) discloses the synthetic route of a Lei Dipawei, Formula II compound
It is one of key intermediate, the quality of the carrying out to subsequent reactions for the Formula II compound and final product-Lei Dipawei
Impact is very big.
Due to molecular structure, Formula II compound crystallinity itself is very poor, needs to be tied by way of becoming salt
Crystalline form, can improve compound crystal property, go the important means of the removal of impurity, improve product quality.
Therefore, this area can be used as the high-purity intermediate of Lei Dipawei synthetic route in the urgent need to exploitation, particularly its
Crystalline solids form, to improve purity and the quality of final product (Lei Dipawei).
Content of the invention
It is an object of the invention to provide a kind of be particularly suitable for produce Lei Dipawei high-purity intermediate and its preparation and
Application.
First aspect present invention, provides a kind of tosilate of compound shown in Formula II
In another preference, described tosilate shown in formula I,
In another preference, described tosilate is crystal formation or amorphous.
In another preference, purity >=99.0% of described tosilate, preferably >=99.2%, more preferably >=
99.5%, most preferably >=99.9%.
In another preference, the crystal formation of described tosilate is crystal formation A, the X-ray powder diffraction of described crystal formation A
Collection of illustrative plates includes 3 or more than 32 θ values being selected from the group：4.9±0.2°、8.2±0.2°、10.0±0.2°、13.7±0.2°、
13.9±0.2°、19.2±0.2°、20.8±0.2°、21.3±0.2°、21.6±0.2°、21.9±0.2°、24.2±0.2°.
In another preference, the X-ray powder diffraction pattern of described crystal formation A includes 3 or more than 3 and is selected from the group
2 θ values：4.9°±0.2°、8.2°±0.2°、10.0°±0.2°、13.9°±0.2°、19.2°±0.2°、20.8°±0.2°.
In another preference, described crystal formation A has the one or more features being selected from the group：
(1) described crystal formation A has the X-ray powder diffraction data selected from table 1；
(2) X-ray powder diffraction pattern of described crystal formation A is substantially as Fig. 1 characterizes；
(3) initial temperature of the differential scanning calorimetry analysis collection of illustrative plates of described crystal formation A is 140.91 ± 3 DEG C；
(4) peak temperature of the differential scanning calorimetry analysis collection of illustrative plates of described crystal formation A is 157.65 ± 3 DEG C；
(5) the differential scanning calorimetry analysis collection of illustrative plates of described crystal formation A is substantially as Fig. 2 characterizes；
(6) the thermogravimetric analysis collection of illustrative plates of described crystal formation A is substantially as Fig. 3 characterizes；And/or
(7) described crystal formation A is single pair of toluene fulfonate.
Second aspect present invention, provides a kind of method of the tosilate prepared as described in the first aspect of the invention,
Described tosilate is amorphous substance, including step：
A () in a solvent, at 0-50 DEG C, Formula II compound and p-methyl benzenesulfonic acid is reacted, generate the right of Formula II compound
The amorphous substance of toluene fulfonate.
In another preference, in described step (a), described solvent is selected from the group：Toluene, acetone, ethanol, tetrahydrochysene furan
Mutter, acetonitrile or a combination thereof.
In another preference, described Formula II compound is 1 with the mol ratio of p-methyl benzenesulfonic acid:0.5-1:1.5, preferably
For 1：1-1：1.2.
In another preference, in described step (a), described reaction temperature is 4-35 DEG C, more preferably for 10-25 DEG C.
In another preference, in described step (a), the described reaction time is 0.1-24 hour, preferably 0.2-20
Hour, more preferably for 0.5-10 hour.
Third aspect present invention, provides a kind of method of the tosilate prepared as described in the first aspect of the invention,
Described tosilate is crystal formation A, including step：
(1), at 4-30 DEG C, the amorphous substance of second aspect present invention methods described preparation is dissolved in solvent, described nothing is fixed
The w/v of shape thing and solvent be 10-1000mg/ml (preferably 50-800mg/ml, more preferably for 80-600mg/ml,
It is most preferably 120-400mg/ml)；
(2) solution of abovementioned steps gained is placed 1-72 hour (preferably 5-36 hour), filtering for crystallizing, thus being obtained
The crystal formation A of described tosilate.
In another preference, in described step (1), described solvent is selected from the group：Toluene, acetone, ethanol, tetrahydrochysene furan
Mutter, acetonitrile or a combination thereof.
In another preference, between described step (1) and step (2), also include step (2-1)：
Crystal seed is added to the solution of step (1) gained, described crystal seed with the percentage by weight of described compound of formula I is
0.1-10%.
In another preference, in described step (2-1), the preparation method of described crystal seed includes step：
(1), at 4-30 DEG C, the amorphous substance of second aspect present invention methods described preparation is dissolved in solvent, Formulas I chemical combination
The w/v of thing and solvent be 10-1000mg/ml (preferably 50-800mg/ml, more preferably for 80-600mg/ml,
It is 120-400mg/ml) goodly；
(2) solution of step (1) gained is placed 1-72 hour (preferably 5-36 hour), filtering for crystallizing, thus being obtained
The crystal seed of described tosilate.
Fourth aspect present invention, provides a kind of purposes of compound of formula I as described in the first aspect of the invention, for preparing
Prevention and/or the medicine for the treatment of hepatitis C (HCV).
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment)
Can be combined with each other between each technical characteristic of body description, thus constituting new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Brief description
Fig. 1 shows the X-ray powder diffraction spectrogram (XRPD) of the crystal formation A of tosilate of the present invention.
Fig. 2 shows the differential scanning calorimetric analysis spectrogram (DSC) of the crystal formation A of tosilate of the present invention.
Fig. 3 shows the thermogravimetic analysis (TGA) spectrogram (TGA) of the crystal formation A of tosilate of the present invention.
Specific embodiment
The present inventor, by extensively in-depth study, is surprised to find that a kind of important centre producing Lei Dipawei first
The amorphous substance of the salt form of body and crystal formation A, especially crystal formation A is easily prepared, contributes to reducing impurity, is more beneficial for improving product
The quality of Lei Dipawei.Complete the present invention on this basis.
Term explanation
Unless otherwise defined, otherwise whole technology used herein and scientific terminology are respectively provided with as art of the present invention
The identical meanings that are generally understood that of those of ordinary skill.
As used herein, when using in mentioning the numerical value specifically enumerated, term " about " means that this value can be from enumerating
Value changes and is not more than 1%.For example, as used herein, statement " about 100 " include 99 and 101 and between whole values (for example,
99.1st, 99.2,99.3,99.4 etc.).
As used herein, term " containing " or " include (comprising) " can be open, semi-enclosed and enclosed.Change
Yan Zhi, described term also include " substantially by ... constitute " or " by ... constitute ".
Compound of formula I
As used herein, term " compound of formula I ", " tosilate " can be with used interchangeably, i.e. Formula II compound
Tosilate, including its amorphous or crystal formation.
As used herein, described " crystal of the present invention ", " crystal formation of the present invention ", " crystal formation of compound of formula I ", " Formulas I
Between the crystal of compound ", " crystal formation of tosilate ", it is used interchangeably, refer both to the tosilate of Formula II compound,
The i.e. crystal formation A of compound of formula I.
Preparation method
The invention provides the preparation method of compound of formula I amorphous substance or crystal formation.
Because crystal formation has higher purity (as >=99%), therefore preferably prepare crystal formation in the present invention, and by this crystalline substance
Type is used as the raw material of Lei Dipawei.
In another preference, the described mode preparing crystal formation is first to prepare compound of formula I amorphous substance, such as this area
Technical staff is referred to the amorphous substance that the teachings of the present invention prepares compound of formula I, then this amorphous substance is used as preparation
The raw material of compound of formula I crystal formation, thus crystallized product is obtained, such as crystal formation A.
In another preference, the method preparing crystal formation is to react Formula II compound with appropriate p-methyl benzenesulfonic acid, anti-
Should among or afterwards directly formed crystal form compound of formula I.
In another preference, the method for preparation compound of formula I crystal formation includes step：
(i) under atent solvent (as toluene, acetone, ethanol, oxolane, acetonitrile or a combination thereof), by Formula II compound
React with p-methyl benzenesulfonic acid, generate the amorphous substance of the tosilate of Formula II compound；
(ii) optionally described amorphous substance is placed a period of time (as placed 1-72 hour, preferably 5-36 hour)；
And/or in described amorphous substance, optionally add crystal seed；
(iii) described reactant mixture is carried out separate (as centrifugal filtration), thus obtaining described tosilate
Crystal formation A.
Crystallization
In the present invention, can be by working solution so that compound of interest reaches hypersaturated state, thus completing to give birth to
The crystallization of product scale.This can be completed by multiple methods, for example, dissolved compound at relatively high temperature, Ran Houleng
But solution is to saturation limit.Or reduced by boiling, atmospheric evaporation, vacuum drying or by some other methods
Liquid volume.Can have the solvent of low solubility or the mixing of such solvent by adding anti-solvent or compound wherein
Thing, to reduce the solubility of compound of interest.Another kind of alternative is to adjust pH value to reduce solubility.Relevant crystallization side
The detailed description in face refers to Crystallization, the third edition, J W Mullens, Butterworth-Heineman
Ltd., 1993, ISBN 0750611294.
If the formation of expectation salt and crystallization occur, if salt is less than dissolution of raw material degree in reaction medium simultaneously, then
Suitable acid or alkali is added to may result in the direct crystallization of required salt.Equally, less than reactant solubility in the form finally wanted
Medium in, the completing of synthetic reaction can make final product direct crystallization.
The optimization of crystallization may include and is inoculated in crystallization medium as crystal seed with the crystal of desired form.In addition, many knots
Crystal method uses the combination of above-mentioned strategy.In a preference, it is at high temperature compound interested to be dissolved in solvent
In, subsequently add the solvent resistant of proper volume by controlled way, so that system is just under saturated level.Now, can add
Enter the crystal seed (and keeping the integrality of crystal seed) of desired form, by system cooling to complete to crystallize.
Main advantages of the present invention are：
(1) preparation method of tosilate (crystal formation or amorphous substance) of the present invention is simple, quick, is easy to big
Large-scale production.
(2) solubility in some solvents for the tosilate of the present invention is especially low, therefore at short notice
Form precipitation or crystallize, therefore purify and separate very convenient and quick.
(3) the crystal formation A of the present invention has very high purity (as >=99%), is especially suitable for use as producing Lei Dipawei's
Intermediate, thus improving the quality of end-product Lei Dipawei, and reduces impurity.
(4) the crystal formation A of the present invention has preferable crystallinity and Impurity removal effect, is conducive to preparing high-quality thunder enlightening
Handkerchief Wei bulk drug.
(5) the crystal formation A of the present invention has preferable thermodynamics and light durability, is conducive to stable quality control and work
Industry is applied.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are percentage by weight and weight
Number.
In following examples, experiment material used and reagent all can obtain from commercially available channel if no special instructions.
Raw material, instrument and universal method
XRD spectrum assay method
X-ray powder diffraction instrument (XRPD)：Bruker D8 Advance X-ray powder diffraction instrument, Cu target, Ka ripple
Long, tube voltage 40KV, tube current 40mA.Sweep limits：3-40°2-Theta；Stepping：0.02°；Sweep speed：1 step/second.
Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) instrument：TA Q2000 differential scanning calorimeter；Temperature range：45-200℃；Heating
Speed：10 DEG C/min.
TGA collection of illustrative plates assay method
NETZSCH TG 209F3 thermogravimetric analyzer；Temperature range：30-400℃；The rate of heat addition：10 DEG C/min.
High performance liquid chromatography (High Performance Liquid Chromatography, HPLC)：
Agilent1260；Chromatographic column：Xbridge C18,4.6 × 150mm；Mobile phase：Trifluoroacetic acid, acetonitrile and water；Inspection
Survey wavelength：220nm.
Formula II compound
It is prepared referring to the method in Chinese invention patent CN2015101179973.
The preparation of embodiment 1 compound of formula I amorphous substance
600mg Formula II compound is added the ethanol adding 5mL in 25ml round-bottomed flask, ultrasonic extremely dissolving.Add
The acetonitrile solution of 1mL1M p-methyl benzenesulfonic acid, resulting solution is placed in Rotary Evaporators and is spin-dried for.
Gained solid is identified through petrographic microscope, confirms as amorphous.
The preparation of embodiment 2 compound of formula I crystal formation A
(1) 40mg Formula II compound is added in 1.5ml centrifuge tube, add 0.2ml ethanol, be subsequently adding equimolar ratio
The ethanol solution of 0.5M p-methyl benzenesulfonic acid, this reactant mixture is slowly volatilized at room temperature, has solids of sedimentation to separate out.Through polarisation
Microscopic examination, confirms as crystal.
(2) centrifuge tube is placed in centrifuge, leaves the heart 5 minutes 12000, remove supernatant, by the solid being separated in
It is dried 1 hour under room temperature.
(3) dried solid is tested to p-methyl benzenesulfonic acid radical content by HPLC, by XRPD, DSC and TGA
Etc. the sign carrying out solid forms.
Result
(1) ion chromatography result shows, in crystal formation A, p-methyl benzenesulfonic acid radical content is 21.8wt%, with compound of formula I
Middle p-methyl benzenesulfonic acid radical theory content (22.3wt%) is substantially identical.It is combined into p-methyl benzenesulfonic acid and Formula II compound during salt
Mol ratio (1:1), show that this crystal is single pair of toluene fulfonate.
(2) XRPD collection of illustrative plates
The XRPD collection of illustrative plates of crystal formation A is substantially as shown in Figure 1.Main diffraction peak and relative intensity are as shown in table 1.
The XRPD data of table 1 crystal formation A
(3) dsc analysis result
The dsc analysis result of crystal formation A is substantially as shown in Figure 2.Result shows, between 50-220 DEG C, the hot-fluid of crystal formation A is bent
Line has an endothermic peak, and its initial temperature is 140.91 DEG C, and peak temperature (peak) is 157.65 DEG C.
(4) TGA analysis result
The TGA analysis result of crystal formation A is substantially as shown in Figure 3.Result shows, weightless 3.38% between 40-140 DEG C, is
Caused by solvent volatilization；Weightless 8.36% between 220-300 DEG C, it is to cause because compound decomposes.
(5) purity analysis
HPLC analysis shows, from Formula II compound react generate single pair of toluene fulfonate crystal formation A after, HPLC purity from
85.6% (Formula II compound) has brought up to >=99.0% (compound of formula I).This result shows, can significantly remove after becoming salt crystallization
Impurity, hence helps to improve the quality of end-product Lei Dipawei.
The crystallization of embodiment 3 compound of formula I amorphous substance
Amorphous for 1g compound of formula I (preparation method is with embodiment 1) is added in 25ml round-bottomed flask, adds 4mL acetonitrile shape
Become settled solution, be subsequently adding about 5mg compound of formula I crystal formation A (preparation method is with embodiment 2) as crystal seed.
This suspension is placed in 2 hour crystallizations are stirred at room temperature, filter to isolate solid, identify through XRPD and confirm this crystal
For crystal formation A.
The salt screening of embodiment 4 compound of formula I
40mg Formula II compound is added to a series of 1.5ml centrifuge tubes, is separately added into 100 μ L ethanol.Ultrasonic extremely dissolving.
Prepare ethanol or the acetonitrile solution of different acid (being shown in Table 2).
The acid solution of equimolar ratio is dripped in compound II solution.Generate if there are precipitation, true by petrographic microscope
Recognize whether precipitation is crystal.If formation settled solution, uncovered it is placed in the slow solvent flashing of room temperature.
Table 2. compound I salt screens
| Acid | Phenomenon | Result |
| Hydrochloric acid | Settled solution | Grease separates out |
| Sulfuric acid | Settled solution | Grease separates out |
| Phosphoric acid | Settled solution | Grease separates out |
| Oxalic acid | Settled solution | Grease separates out |
| Fumaric acid | Settled solution | Grease separates out |
| P-methyl benzenesulfonic acid | Solids of sedimentation separates out | Single pair of toluene fulfonate |
Summary result shows, the crystal formation of compound of formula I (i.e. the single pair of toluene fulfonate of Formula II compound) is especially suitable
Share the intermediate making to prepare Lei Dipawei.
The all documents referring in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned instruction content having read the present invention, those skilled in the art can
To make various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. the tosilate of compound shown in a kind of Formula II,
2. tosilate as claimed in claim 1 is it is characterised in that described tosilate is crystal formation or no fixed
Shape.
3. tosilate as claimed in claim 2 it is characterised in that described tosilate crystal formation be crystal formation A,
The X-ray powder diffraction pattern of described crystal formation A includes 3 or more than 32 θ values being selected from the group：4.9±0.2°、8.2±
0.2°、10.0±0.2°、13.7±0.2°、13.9±0.2°、19.2±0.2°、20.8±0.2°、21.3±0.2°、21.6±
0.2°、21.9±0.2°、24.2±0.2°.
4. tosilate as claimed in claim 3 it is characterised in that described crystal formation A have being selected from the group or
Multiple features：
(1) X-ray powder diffraction pattern of described crystal formation A includes 3 or more than 32 θ values being selected from the group：4.9°±0.2°、
8.2°±0.2°、10.0°±0.2°、13.9°±0.2°、19.2°±0.2°、20.8°±0.2°；
(2) described crystal formation A has the X-ray powder diffraction data selected from table 1；
(3) X-ray powder diffraction pattern of described crystal formation A is substantially as Fig. 1 characterizes；
(4) initial temperature of the differential scanning calorimetry analysis collection of illustrative plates of described crystal formation A is 140.91 ± 3 DEG C；
(5) peak temperature of the differential scanning calorimetry analysis collection of illustrative plates of described crystal formation A is 157.65 ± 3 DEG C；
(6) the differential scanning calorimetry analysis collection of illustrative plates of described crystal formation A is substantially as Fig. 2 characterizes；
(7) the thermogravimetric analysis collection of illustrative plates of described crystal formation A is substantially as Fig. 3 characterizes；And/or
(8) described crystal formation A is single pair of toluene fulfonate.
5. a kind of method preparing tosilate as claimed in claim 1 is it is characterised in that described tosilate
It is amorphous substance, including step：
A () in a solvent, at 0-50 DEG C, Formula II compound and p-methyl benzenesulfonic acid is reacted, generate Formula II compound to toluene
The amorphous substance of sulfonate.
6. method as claimed in claim 5 is it is characterised in that described solvent is selected from the group：Toluene, acetone, ethanol, tetrahydrochysene furan
Mutter, acetonitrile or a combination thereof.
7. method as claimed in claim 5 is it is characterised in that described Formula II compound is 1 with the mol ratio of p-methyl benzenesulfonic acid:
0.5-1:1.5.
8. a kind of method preparing tosilate as claimed in claim 1 is it is characterised in that described tosilate
It is crystal formation A, including step：
(1) at 4-30 DEG C, by claim 5 methods described preparation amorphous substance be dissolved in solvent, described amorphous substance with molten
The w/v of agent is 10-1000mg/ml；
(2) solution of abovementioned steps gained is placed 1-72 hour, filtering for crystallizing, thus the crystalline substance of described tosilate is obtained
Type A.
9. method as claimed in claim 8 is it is characterised in that in described step (1), described solvent is selected from the group：Toluene, third
Ketone, ethanol, oxolane, acetonitrile or a combination thereof.
10. a kind of purposes of tosilate as claimed in claim 1 is it is characterised in that for preparation prevention and/or control
Treat the medicine of hepatitis C (HCV).
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Citations (5)
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|---|---|---|---|---|
| WO2011156757A1 (en) * | 2010-06-10 | 2011-12-15 | Gilead Sciences, Inc. | Combination of anti-hcv compounds with ribavirin for the treatment of hcv |
| WO2012068234A2 (en) * | 2010-11-17 | 2012-05-24 | Gilead Sciences, Inc. | Antiviral compounds |
| WO2012087596A1 (en) * | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CN104244945A (en) * | 2011-09-16 | 2014-12-24 | 吉利德法莫赛特有限责任公司 | Methods for treating hcv |
| CN104829599A (en) * | 2015-03-17 | 2015-08-12 | 上海众强药业有限公司 | Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir |
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| WO2011156757A1 (en) * | 2010-06-10 | 2011-12-15 | Gilead Sciences, Inc. | Combination of anti-hcv compounds with ribavirin for the treatment of hcv |
| WO2012068234A2 (en) * | 2010-11-17 | 2012-05-24 | Gilead Sciences, Inc. | Antiviral compounds |
| WO2012087596A1 (en) * | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CN104244945A (en) * | 2011-09-16 | 2014-12-24 | 吉利德法莫赛特有限责任公司 | Methods for treating hcv |
| CN104829599A (en) * | 2015-03-17 | 2015-08-12 | 上海众强药业有限公司 | Preparation method of ledipasvir and derivative thereof, and intermediate compound for preparing the ledipasvir |
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Denomination of invention: A single para toluenesulfonic acid salt intermediate of Remdesivir, its crystal form and preparation method Granted publication date: 20191210 Pledgee: China Minsheng Banking Corp Shanghai branch Pledgor: SHANGHAI FOREFRONT PHARMCEUTICAL Co.,Ltd. Registration number: Y2024310000803 |