CN111004210A - Compound single crystal and method for producing same - Google Patents

Compound single crystal and method for producing same Download PDF

Info

Publication number
CN111004210A
CN111004210A CN201911010725.8A CN201911010725A CN111004210A CN 111004210 A CN111004210 A CN 111004210A CN 201911010725 A CN201911010725 A CN 201911010725A CN 111004210 A CN111004210 A CN 111004210A
Authority
CN
China
Prior art keywords
single crystal
compound
temperature
supercooled melt
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN201911010725.8A
Other languages
Chinese (zh)
Inventor
陆明
黄思咏
李锡祯
欧霄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Yat Sen University
National Sun Yat Sen University
Original Assignee
National Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National Sun Yat Sen University filed Critical National Sun Yat Sen University
Priority to CN201911010725.8A priority Critical patent/CN111004210A/en
Publication of CN111004210A publication Critical patent/CN111004210A/en
Priority to CN202011137678.6A priority patent/CN112250663B/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 relates to a compound single crystal and a preparation method thereof. The preparation method comprises the following steps: 1) melting the compound to obtain supercooled melt droplets having a diameter of 100 μm-5 mm; 2) making supercooled melt small liquid drop at T1Spontaneous nucleation at temperature to obtain a single crystal nucleus of the target crystal form of the compound, Tg<T1<Tm，TgIs the glass transition temperature, T, of the target crystal form of the compoundmIs the melting point of the target crystalline form of the compound; 3) if no single crystal nucleus of the target crystal form of one compound is obtained, the temperature is changed from T1Is raised to T2Hold T1<T2<TmUntil a single crystal nucleus of the compound with the target crystal form is obtained; 4) dripping supercooled melt containing a single crystal nucleus into T3Temperature ofThe method can successfully analyze the single crystal structure of ROY Y04 crystal form and the single crystal structure of nifedipine gamma crystal form which are puzzling the industry for years, and can culture the single crystal of the heat-sensitive drug Verofinib α crystal form and analyze the single crystal structure.

Description

Compound single crystal and method for producing same
Technical Field
The invention relates to the field of single crystal structure analysis, in particular to a compound single crystal and a preparation method thereof.
Background
The single crystal structure determination is a key step of supramolecular action processes such as resolving the polymorphic crystal structure of a compound, determining the absolute configuration of a chiral compound, and defining the binding mechanism of a drug and a target. Single crystal X-ray diffraction is currently the predominant technique for resolving single crystal structures, the key step being the cultivation of single crystals of sufficiently large size (>50 μm) and sufficiently good quality. The failure of many single crystal structures to resolve successfully is often limited by the critical step of single crystal growth.
Solution crystallization is a traditional method for single crystal culture, but has the defects of more variables (solvent types, supersaturation degree, temperature, solvent volatilization rate and the like) and long period. Some crystal forms, which can be obtained only from a melt and cannot be obtained from a solution, cannot be cultured from a solvent, and therefore, the crystal structure cannot be resolved, such as the Y04 crystal form of olanzapine intermediate 5-methyl 2- [ (2-nitrobenzene) amino ] -3-thiophenecarbonitrile (ROY) and the gamma crystal form of nifedipine.
Problems commonly encountered with melt crystallization of single crystals are: 1) polycrystalline intergrowth and cross nucleation are very common phenomena in melt crystallization, making it extremely difficult to cultivate single crystals from supercooled melts; 2) the metastable crystal form is easy to be transformed into a stable crystal form at high temperature; 3) for heat sensitive drugs, melt crystallization is prone to chemical degradation problems.
For example: ROY form Y04 was first discovered and reported in 2004 from the melt by the professor group of McCardigan university, Madison division residual, Wis.A. (Journal of the American Chemical Society 2005,127: 9881-9885). In 15 years, many subjects focus on the crystal structure research of ROY crystal forms, but the single crystal structure of Y04 crystal form (CrystEngComm 2019,21:2080-2088) cannot be resolved all the time, because the spontaneous nucleation of Y04 crystal form from melt is usually accompanied with other crystal forms to nucleate together, and the spontaneous nucleation of Y04 crystal form on the surface of the crystal form is often crossed to form R crystal form, and the growth rate of the R crystal form is faster than that of Y04 crystal form, so that the Y04 crystal form is often enclosed. At the same time, the Y04 crystal form is solid-solid phase transformed into YT04 crystal form. Even with the partial melting method recently reported by the present inventors, it was not possible to cultivate a single crystal structure of form pay Y04 because a sample containing only form Y04 could not be prepared by both spontaneous nucleation and seeding.
Nifedipine gamma crystal form was first discovered and reported from the melt in 1977 (Archiv der Pharmazie1977,310(2): 116-; 118), but its crystal structure has been an unblended puzzle in the industry for 42 years despite many literature studies on its crystallization behavior, because gamma crystal form can only be obtained in polycrystalline form by melt crystallization and always intergrowth with β crystal form polycrystals, β crystal form induces nucleation of α crystal form, the latter growth rate is much faster than gamma crystal form, and once both are in contact, gamma crystal form is transformed into a more stable crystal form, thus single crystals of gamma crystal form cannot be cultured.
The Verofinib is a heat-sensitive drug, the chemical property near the melting point is unstable, the single Crystal structure of the stable Crystal form is not reported in the literature (Crystal Growth & Design 2016,16: 6033-.
Disclosure of Invention
Aiming at the problems, the invention provides a compound single crystal and a preparation method thereof, wherein nucleation of each crystal form is separated into independent liquid drops from supercooled melt liquid drops, so that mutual interference (including robbing molecular resources, cross nucleation and solid-solid phase transformation) of each crystal form in the growth process is avoided, and further the single crystal of the target crystal form of the compound can be selectively cultured, the single crystal structure of the ROY Y04 crystal form and the single crystal structure of the nifedipine gamma crystal form which are troubling the industry for years are successfully analyzed, and the single crystal of the heat-sensitive drug Verofini α crystal form is cultured and the single crystal structure is analyzed.
The specific technical scheme is as follows:
a method for producing a compound single crystal, comprising the steps of:
1) melting the compound to obtain supercooled melt droplets having a diameter of 100 μm-5 mm;
2) making said supercooled melt small droplets at T1Spontaneous nucleation at temperature to obtain a single crystal nucleus of the target crystal form of the compound, Tg<T1<TmSaid T isgIs the glass transition temperature of the target crystal form of the compound, the TmIs the melting point of the target crystalline form of the compound;
3) if a single crystal nucleus of the target crystal form of the compound is not obtained, the temperature is increased from T1Is raised to T2Hold T1<T2<TmUntil a single crystal nucleus of the compound with the target crystal form is obtained;
4) dropping the supercooled melt containing a single crystal nucleus into T3Culturing at a temperature to obtain the single crystal.
In one embodiment, step 1) is performed by melting the compound to obtain supercooled melt droplets having a diameter of 100 μm to 500 μm.
In one embodiment, the step 4) is specifically:
a) dropping the supercooled melt containing a single crystal nucleus into T3Culturing at constant temperature;
b) if no amorphous chemical bifurcation appears, obtaining a single crystal;
c) if amorphous chemical bifurcation occurs, repeating the steps 1), 2) and 3) until one compound target crystal form single crystal nucleus is obtained, and dripping the supercooled melt containing one single crystal nucleus into T4Culturing at constant temperature to obtain single crystal; said temperature T4Must satisfy T3＜T4＜Tm。
In one embodiment, the method for preparing the compound single crystal comprises the following steps:
1) melting olanzapine intermediate 5-methyl 2- [ (2-nitrophenyl) amino ] -3-thiophenecarbonitrile at 126 + -1 ℃ to obtain supercooled melt droplets having a diameter of 100-500 μm;
2) allowing spontaneous nucleation of said supercooled melt droplets at a temperature of 22 + -5 ℃ to obtain a single crystal nucleus of the Y04 crystal form of olanzapine intermediate 5-methyl 2- [ (2-nitrophenyl) amino ] -3-thiophenecarbonitrile;
3) and (3) culturing the supercooled melt droplets containing a single crystal nucleus at the temperature of 70 +/-3 ℃ to obtain the Y04 crystal form single crystal of the olanzapine intermediate 5-methyl 2- [ (2-nitrobenzene) amino ] -3-thiophenecarbonitrile.
According to the method, a large number of supercooled melt small droplets are obtained by melting a compound, and as different crystal forms such as YN crystal forms and ON crystal forms can be nucleated in different small droplets, random nucleation events in the melt can be separated to a great extent by the large number of supercooled melt small droplets, so that the Y04 crystal forms have a chance to be nucleated in an independent supercooled melt small droplet and are prevented from being interfered by other crystal forms; meanwhile, the supercooled melt droplets containing a single crystal nucleus are transferred to a proper growth temperature, so that the problems of cross nucleation and solid-solid phase transformation are solved, a single crystal of the Y04 crystal form is successfully cultured, and the single crystal structure is resolved.
In one embodiment, the method for preparing the compound single crystal comprises the following steps:
1) nifedipine is melted at 181 +/-1 ℃ until supercooled melt droplets with the diameter of 100 mu m-5mm are obtained;
2) spontaneous nucleation of the supercooled melt droplets is carried out at the temperature of 115 +/-15 ℃ to obtain a nifedipine gamma crystal form monocrystal crystal nucleus;
3) and (3) culturing the supercooled melt droplet containing a single crystal nucleus at the temperature of 115 +/-15 ℃ to obtain the nifedipine gamma crystal form single crystal.
The method comprises the steps of obtaining a large number of supercooled melt small drops through a molten compound, wherein nifedipine gamma crystal and nifedipine β crystal nucleation can occur in different small drops, or the small drops can not nucleate, or two crystal nuclei can form in the same small drop, separating nucleation of nifedipine gamma crystal form and nifedipine β crystal form in different small drops by using the small drops, avoiding interference of nifedipine gamma crystal form with nifedipine β crystal form in a slow growth process, keeping the supercooled melt state, and randomly nucleating depending on probability, thereby successfully preparing the nifedipine gamma crystal form single crystal and resolving a single crystal structure.
1) Placing Verofinib at 276 +/-1 ℃ for 1s-2s, and melting the Verofinib until obtaining supercooled melt droplets with the diameter of 100 mu m-3 mm;
2) spontaneous nucleation of the supercooled melt droplets is carried out at the temperature of 264 +/-1 ℃ to obtain a single crystal nucleus of the vemurafenib α crystal form;
3) and (3) culturing the supercooled melt droplets containing a single crystal nucleus at the temperature of 269 +/-1 ℃ to obtain the Vemurafenib α crystal form single crystal.
The method adopts a method of spontaneous nucleation to form a single crystal nucleus, a melt droplet can be obtained only by melting a vemurafenib powdery sample near a melting point for a few seconds, then homogeneous nucleation is induced below the melting point, after a single crystal nucleus is formed, the temperature is immediately raised to a proper temperature, a vemurafenib α crystal form single crystal with a large enough size is cultured, and the single crystal structure is successfully analyzed.
The invention also provides a compound single crystal prepared by the preparation method.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a brand-new supercooled melt droplet-based method for culturing single crystals, which can quickly obtain large-size and high-quality compound single crystals from melt droplets by using a very small amount of samples. Successfully resolves 3 single crystal structures which can not be resolved in the industry for years, including 5-methyl 2- [ (2-nitrobenzene) amino as an intermediate of olanzapine]-3-thiophenecarbonitrile (ROY) single crystal of crystal form Y04, nifedipine gamma and vemurafenib α general idea is that molten compounds obtain supercooled melt droplets, which are made at T1Spontaneous nucleation at temperature to obtain a single crystal nucleus, and rapidly transferring to T3Culturing at constant temperature to obtain single crystal with enough size. The method does not need to use a solvent, and can carry out real-time visual monitoring on the single crystal culture process.
The above method is suitable for crystal forms of compounds which can form single crystal nuclei by spontaneous nucleation from a melt, for compounds which are not decomposed or not seriously decomposed by heating before melting and compounds which are not sublimated or not seriously sublimated before melting, for crystal forms which can be obtained only by melt crystallization or compounds which are difficult to grow single crystals from a solution, and for compounds which can grow single crystals by a solution method. The method is suitable for compound crystal forms which can form single crystal nucleuses from undercooled melts by spontaneous nucleation at proper temperature. The method has the advantages of less variable, high efficiency and strong controllability, and can selectively culture the single crystal of the target crystal form of the compound.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
All temperatures referred to herein are, unless otherwise specified, degrees celsius.
Crystallization involves two steps, nucleation and crystal growth. The dependence of these two steps on supercooling (difference between melting point and experimental temperature) is different. Under low supercooling degree, the supercooled melt has small viscosity, high molecular activity and small crystallization driving force, and is not easy to nucleate, but the crystal growth rate is fast (the crystal growth rate is rapidly slowed down when the supercooling degree is very low); at high supercooling degree, the supercooled melt has large viscosity, low molecular mobility and full crystal growth, but the crystal driving force is large, so that nucleation is easy, and secondary nucleation (noncrystal chemical fork) at the front edge of the crystal in the crystal growth process usually leads to the formation of spherulites which are considered to be aggregates of a plurality of single crystals.
Based on the principle, the invention uses the super-cooled melt at T1Spontaneous nucleation at temperature to obtain single crystal nuclei, which are transferred to T before they undergo amorphous chemical crossing3[Tm-T3<0.1(Tm+273℃)]And (3) carrying out constant-temperature culture at the temperature, and limiting the size of the small drops of the melt to ensure that the target crystal form and the non-target crystal form nucleate in different small drops, thereby obtaining the single crystal sample of the target crystal form of the compound. Wherein, the physical obstruction of the small droplets is crucial to the successful culture of the single crystal; the control of the nucleation temperature is important for successfully obtaining single crystal nuclei; the selection of the temperature for the cultivation is crucial for the cultivation of single crystals.
The present invention has different treatment strategies for compound systems with different characteristics. The method comprises the following specific steps:
example 1
A preparation method of a single crystal of 5-methyl 2- [ (2-nitrobenzene) amino ] -3-thiophenecarbonitrile (ROY) as an olanzapine intermediate in a Y04 crystal form comprises the following steps:
step 1) placing raw material medicine powder of olanzapine intermediate 5-methyl 2- [ (2-nitrobenzene) amino ] -3-thiophene formonitrile (ROY) in a hot table with the temperature preset to 125 ℃, and melting to prepare a plurality of supercooled melt droplets with the diameter of about 100-500 mu m.
Step 2) transferring the supercooled melt droplets to a 22 ℃ hot stage at a constant temperature until a single crystal nucleus of the Y04 crystal form of the olanzapine intermediate 5-methyl 2- [ (2-nitrophenyl) amino ] -3-thiophenecarbonitrile is observed.
And 3) quickly transferring the supercooled melt droplets containing a single crystal nucleus in the step 2 to a hot stage at 70 ℃, and culturing at constant temperature for 20min to obtain the Y04 crystal form single crystal.
Example 2
A preparation method of nifedipine gamma crystal form single crystal comprises the following steps:
step 1) melting a little nifedipine bulk drug powder at 180 ℃ to prepare a plurality of supercooled melt droplets with the diameter of about 100 mu m-5 mm.
And 2) transferring the supercooled melt small drops to a Linkam hot table with preset temperature of 125 ℃ for constant temperature until a nifedipine gamma crystal form single crystal nucleus is observed.
And 3) continuously keeping the temperature constant on a hot stage at 125 ℃ to ensure that the nifedipine monocrystal gradually grows up to obtain the nifedipine gamma crystal form monocrystal.
Example 3
A preparation method of a vemurafenib α crystal form single crystal comprises the following steps:
step 1) placing a small amount of Virofenib powder samples on a glass slide, placing the glass slide on a hot table with the preset temperature of 277 ℃, keeping the temperature for 1s, and completely melting the samples to obtain a plurality of supercooled melt droplets with the diameter of about 100 mu m-3 mm.
And 2) quickly transferring the melt small drops to a Linkam hot table with the temperature preset to be 265 ℃ to wait for spontaneous nucleation of the melt small drops to obtain the supercooled melt small drops containing one crystal nucleus of the Virofenib α crystal form single crystal.
And 3) heating the supercooled melt droplets containing a single crystal nucleus to 270 ℃ at a speed of 150 ℃/min, and culturing at a constant temperature until the single crystal grows gradually to obtain the Verofenib α crystal form single crystal.
Note: the nucleation and growth temperatures of the crystalline form are very close to the melting point (the degree of supercooling is very low), so the nucleation induction period and growth rate can be very random.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (7)

1. A method for producing a compound single crystal, comprising the steps of:
1) melting the compound to obtain supercooled melt droplets having a diameter of 100 μm-5 mm;
2) making said supercooled melt small droplets at T1Spontaneous nucleation at temperature to obtain a single crystal nucleus of the target crystal form of the compound, Tg<T1<TmSaid T isgIs the glass transition temperature of the target crystal form of the compound, the TmIs the melting point of the target crystalline form of the compound;
3) if a single crystal nucleus of the target crystal form of the compound is not obtained, the temperature is increased from T1Is raised to T2Hold T1<T2<TmUntil a single crystal nucleus of the compound with the target crystal form is obtained;
4) dropping the supercooled melt containing a single crystal nucleus into T3Culturing at a temperature to obtain the single crystal.
2. The method of producing a compound single crystal according to claim 1, wherein in the step 1), the compound is melted to obtain supercooled melt droplets having a diameter of 100 μm to 500 μm.
3. The method for producing a compound single crystal according to claim 1, wherein the step 4) is specifically:
a) dropping the supercooled melt containing a single crystal nucleus into T3Culturing at constant temperature;
b) if no amorphous chemical bifurcation appears, obtaining a single crystal;
c) if amorphous chemical bifurcation occurs, repeating the steps 1), 2) and 3) until one compound target crystal form single crystal nucleus is obtained, and dripping the supercooled melt containing one single crystal nucleus into T4Culturing at constant temperature to obtain single crystal; said temperature T4Must satisfy T3＜T4＜Tm。
4. A method for producing a compound single crystal according to any one of claims 1 to 3, characterized by comprising the steps of:
1) melting olanzapine intermediate 5-methyl 2- [ (2-nitrophenyl) amino ] -3-thiophenecarbonitrile at 126 ± 1 ℃ to obtain supercooled melt droplets having a diameter of 100 μm to 500 μm;
2) allowing spontaneous nucleation of said supercooled melt droplets at a temperature of 22 + -5 ℃ to obtain a single crystal nucleus of the Y04 crystal form of olanzapine intermediate 5-methyl 2- [ (2-nitrophenyl) amino ] -3-thiophenecarbonitrile;
3) and (3) culturing the supercooled melt droplets containing a single crystal nucleus at the temperature of 70 +/-3 ℃ to obtain the Y04 crystal form single crystal of the olanzapine intermediate 5-methyl 2- [ (2-nitrobenzene) amino ] -3-thiophenecarbonitrile.
5. The method for producing a compound single crystal according to claim 1 or 3, characterized by comprising the steps of:
1) nifedipine is melted at 181 +/-1 ℃ until supercooled melt droplets with the diameter of 100 mu m-5mm are obtained;
2) spontaneous nucleation of the supercooled melt droplets is carried out at the temperature of 115 +/-15 ℃ to obtain a nifedipine gamma crystal form monocrystal crystal nucleus;
3) and (3) culturing the supercooled melt droplet containing a single crystal nucleus at the temperature of 115 +/-15 ℃ to obtain the nifedipine gamma crystal form single crystal.
6. The method for producing a compound single crystal according to claim 1 or 3, characterized by comprising the steps of:
1) placing the vemurafenib at 276 +/-1 ℃ for 1s-2s for melting until obtaining supercooled melt droplets with the diameter of 100 mu m-3 mm;
2) spontaneous nucleation of the supercooled melt droplets is carried out at the temperature of 264 +/-1 ℃ to obtain a single crystal nucleus of the vemurafenib α crystal form;
3) and (3) culturing the supercooled melt droplets containing a single crystal nucleus at the temperature of 269 +/-1 ℃ to obtain the Vemurafenib α crystal form single crystal.
7. A compound single crystal produced by the production method according to any one of claims 1 to 6.
CN201911010725.8A 2019-10-23 2019-10-23 Compound single crystal and method for producing same Withdrawn CN111004210A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201911010725.8A CN111004210A (en) 2019-10-23 2019-10-23 Compound single crystal and method for producing same
CN202011137678.6A CN112250663B (en) 2019-10-23 2020-10-22 Compound single crystal and method for producing same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911010725.8A CN111004210A (en) 2019-10-23 2019-10-23 Compound single crystal and method for producing same

Publications (1)

Publication Number Publication Date
CN111004210A true CN111004210A (en) 2020-04-14

Family

ID=70110908

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201911010725.8A Withdrawn CN111004210A (en) 2019-10-23 2019-10-23 Compound single crystal and method for producing same
CN202011137678.6A Active CN112250663B (en) 2019-10-23 2020-10-22 Compound single crystal and method for producing same

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202011137678.6A Active CN112250663B (en) 2019-10-23 2020-10-22 Compound single crystal and method for producing same

Country Status (1)

Country Link
CN (2) CN111004210A (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276592A (en) * 2011-06-17 2011-12-14 大连理工大学 Related substance of olanzapine and preparation method and analytical method thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1670827C3 (en) * 1967-03-20 1974-10-24 Bayer Ag, 5090 Leverkusen 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine
GB9009229D0 (en) * 1990-04-25 1990-06-20 Lilly Industries Ltd Pharmaceutical compounds
JP3369394B2 (en) * 1996-03-14 2003-01-20 日本電信電話株式会社 Crystal preparation method
CN102603581B (en) * 2005-06-22 2015-06-24 普莱希科公司 Pyrrolo[2,3-b] pyridine derivatives as protein kinase inhibitors
CN110747511A (en) * 2019-10-23 2020-02-04 中山大学 Compound single crystal and method for producing same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276592A (en) * 2011-06-17 2011-12-14 大连理工大学 Related substance of olanzapine and preparation method and analytical method thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JONAS NYMAN等: "Accuracy and reproducibility in crystal structure prediction: the curious case of ROY", 《CRYSTENGCOMM》 *
MING LU等: "Vemurafenib: A Tetramorphic System Displaying Concomitant Crystallization from the Supercooled Liquid", 《CRYST. GROWTH DES.》 *
SHUANG CHEN等: "New Polymorphs of ROY and New Record for Coexisting Polymorphs of Solved Structures", 《J. AM. CHEM. SOC.》 *
王文礼 等: "二苯甲酮晶体的生长习性预测和实验研究", 《人工晶体学报》 *
王文礼 等: "二苯甲酮晶体的过冷熔体生长及性能", 《人工晶体学报》 *

Also Published As

Publication number Publication date
CN112250663A (en) 2021-01-22
CN112250663B (en) 2022-08-19

Similar Documents

Publication Publication Date Title
JPH0152359B2 (en)
CN104109904A (en) Seeding method of sapphire crystal growth kyropoulos method
EP0362440A2 (en) Process for crystal growth from solution
JP6053018B2 (en) Crystal growth method
KR20070039607A (en) Method of growing single crystals from melt
US4793894A (en) Process for crystal growth from solution
CN111004210A (en) Compound single crystal and method for producing same
JP2006143555A (en) Method for manufacturing silicon carbide single crystal
CN101514481A (en) Method for growing a BaAlBO3F2 crystal by fusing agent
CN110067024A (en) Photoelectric functional crystal M3RE(PO4)3And preparation method thereof
CN110747511A (en) Compound single crystal and method for producing same
CN103290466B (en) A kind of YAB crystal growth flux and YAB growing method
CN103668455B (en) The grower of a kind of lbo crystal and growing method
RU2740126C1 (en) Method of growing monocrystals 57febo3 of high structural perfection
US11597713B2 (en) Method for purifying crystals using solvent vapors
KR101542346B1 (en) Method and apparatus for purifying organic materials using ionic liquid
Chen et al. Growth of lead molybdate crystals by vertical Bridgman method
US7001458B2 (en) Process for growing of optical fluorite single crystals
RU2471896C1 (en) Method of growing bulk monocrystals of alexandrite
RU2556114C2 (en) Method of growing sodium-bismuth molybdate monocrystals
Tsvetkov et al. The major problems of seeding and growth of barium borate crystals in terms of new data on phase relations in BaO–B2O3–Na2O system
CN101831700A (en) Quick growth method for potassium dihydrogen phosphate single crystal
RU2542313C2 (en) Method for rubidium-bismuth molybdate monocrystal growing
US10308626B1 (en) Crystal purification in a glass or metal container
Grunwald Crystalline growth of monoclinic selenium

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication
WW01 Invention patent application withdrawn after publication

Application publication date: 20200414