CN105523993A - N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof - Google Patents
N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof Download PDFInfo
- Publication number
- CN105523993A CN105523993A CN201510996797.XA CN201510996797A CN105523993A CN 105523993 A CN105523993 A CN 105523993A CN 201510996797 A CN201510996797 A CN 201510996797A CN 105523993 A CN105523993 A CN 105523993A
- Authority
- CN
- China
- Prior art keywords
- crystal
- methyl
- luorobenzyl
- base
- preparation
- 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.)
- Pending
Links
Classifications
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- 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 preparation method of N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and belongs to the technical field of drug crystal forms. The method comprises the following steps: 1, grinding N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form A; 2, heating the obtained ground solid in an inert gas to 130-150DEG C; and 3, cooling the heated solid to 15-30DEG C to obtain the N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C. The method has the advantages of simple operation and low cost, and provides a new approach for preparation of stable crystal forms of N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate.
Description
Technical field
The invention belongs to drug crystal forms technical field, being specifically related to a kind of is that raw material prepares the short-cut method of this tartrate stable crystal form C by grinding post-heating with a kind of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation.
Background technology
WO01/66521 describes N-azacycloalkyl-N-aralkyl ureas and carboxylic acyloxy amine, they constitutes the class novel cpd effectively suppressing monoamine receptor (comprising the 5-hydroxytryptamine receptor of 5-HT2A subclass) active.The example of the disease state of this compounds can be used to include but not limited to, neuropsychiatric disease, dysthymia disorders, anxiety, somnopathy, limited appetite, affective disorder syndromes.Useful N-azacycloalkyl-N-aralkyl urea is N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea, and its structural formula as shown in Equation 1.
The compound of formula 1 has low solubility in water, water miscible N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate is suitable form with regard to the preparation of medicinal compositions and preparation, and its structural formula as shown in Equation 2.
The compound of formula 2 has multiple crystal formation, comprises crystal form A, B, C and solvate thereof, and wherein crystal C is the most stable crystal formation.Patent CN101778821A discloses by adding crystal seed in the brilliant method preparing crystal C of resuspension procedure transfer.
Summary of the invention
But the technical problem that the method preparing crystal C recorded in CN101778821A exists is that requirement solvent for use is degassed and carry out under oxygen-free environment, need strict operation and consuming time longer.In order to solve this technical problem the novel method providing one to prepare N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate stable crystal form.
Be aided with the thermal stresses method of heating after the present invention relates to grinding, the stable crystal form for preparation N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate provides a new approach.
Specifically, the invention provides following technical scheme:
A kind of preparation method of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate crystal C, it is characterized in that, with the A crystal formation of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate for raw material, the method comprises the following steps:
(1) by N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation grinding;
(2) solid after grinding is heated to 130 ~ 150 DEG C under an inert gas; With
(3) crystal C that namely 15-30 DEG C obtain N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate is cooled to.
Preferably, wherein in step (1), described grinding refers to that it is 0.3-10 μm that described A crystal formation is ground to particle size range.
Preferably, wherein in step (2), when being heated to 30 ~ 150 DEG C, keep 10-40min.
Preferably, wherein in step (3), be cooled to room temperature and namely obtain described crystal C.
Preferably, in wherein said step (1), 40 ~ 60min is carried out in described grinding.
Preferably, wherein in step (2), described rare gas element is nitrogen or argon gas.
N-(4-luorobenzyl)-N-(1-methyl piperidine-4-the base)-N ' that the present invention also provides a kind of above-mentioned preparation method to obtain-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate crystal C, it is characterized in that, described crystal C represents to have following characteristic diffraction peak with diffraction angle 2 θ ° ± 0.1: 7.3 °, 8.2 °, 11.9 °, 12.7 °, 13.4 °, 14.3 °, 15.0 °, 16.0 °, 16.7 °, 17.1 °, 18.2 °, 18.8 °, 19.3 °, 20.2 °, 20.7 °, 21.0 °, 21.6 °, 22.5 °, 23.5 °, 23.9 °, 24.6 °, 25.4 °, 26.0 °, 27.4 °, 29.0 ° and 30.4 °.
The present invention also provides described crystal C for the preparation of the application in medicine in treatment neuropsychiatric disease, nerve degenerative diseases or dysthymia disorders or somnopathy etc.
Beneficial effect of the present invention: the present invention adopts thermal stresses legal system for the crystal C of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate.Compared with prior art, the present invention has following features: technique is simply efficient, and do not use solvent, energy-conservation, environmental friendliness, simple to operate, controllability is strong.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffractogram of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation.
Fig. 2 is the X-ray powder diffractogram of the C crystal form that the inventive method embodiment 2 obtains.
Fig. 3 is the infrared spectrum of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation.
Fig. 4 is the infrared spectrum of the C crystal form that the inventive method embodiment 2 obtains.
Fig. 5 is the DSC figure of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation.
Fig. 6 is the DSC figure of the C crystal form that the inventive method embodiment 2 obtains.
Embodiment
In prior art, N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) this compound of urea tartrate is used for the treatment of neuropsychiatric disease, nerve degenerative diseases, dysthymia disorders, anxiety, somnopathy, limited appetite, during affective disorder syndromes, there is the high and demand requiring stability high of solubleness in water, the crystal C of wherein N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate compound because of the high-dissolvability in water and because of its stability high thus be highly suitable for medicine manufacture and preparation in.The present invention is directed in prior art when preparing crystal C and there is complicated operation and longer and problem of environmental pollution consuming time, provide a kind of solvent that do not need newly and the crystal form A of above-claimed cpd can be converted into crystal C only by grinding, intensification and cooling simple operations, the stability of crystal C compares crystal form A or crystal form B significantly improves.
In the preferred embodiment of the present invention, the invention provides the preparation method of following crystal C, it comprises the following steps:
(1), take appropriate N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation and fully grind 40 ~ 60min in mortar.
(2), by the solid after grinding be heated to 130 ~ 150 DEG C under an inert gas, and keep for some time.
(3), room temperature is slowly cooled to, by gained solid conservation, obtain the stable crystal form C product of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate.
Above-mentioned heating is carried out under an inert gas, and rare gas element is nitrogen or argon gas.
In the present invention, the above-mentioned crystal C compound prepared according to the inventive method is used for the treatment of neuropsychiatric disease recited above, comprises the psychosis of hypertension secondary, neuropathic pain, migraine, vasospasm and local asphyxia, motor tic, trembles, psychomotor retardation, bradykinesia etc.; Above-mentioned crystal C compound of the present invention is used for the treatment of described nerve degenerative diseases recited above and comprises Parkinson's disease, alzheimer disease, myodystonia, Spinocerebellar Atrophy etc.
Any method that source chemicals crystal form A used in the present invention can adopt pharmaceutical field known prepares, the method preparation that such as can provide according to patent CN101778821A.
Crystal C compound prepared by the present invention can adopt the receivable auxiliary material of the medicine of this area routine and or carrier make pharmaceutical preparation and be used for the treatment of above-mentioned various psychotic disorder or various neurological disorder symptom.Dosage required during the consumption of activeconstituents C crystal form depends on preparation type and administration in the pharmaceutical preparation made.
Below by embodiment, the preparation method to N-of the present invention (4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate crystal C is further elaborated.
Wherein, used in embodiment below the present invention main measuring methods is described as follows:
X-ray diffraction powder strength measures: X ' the pert type x-ray powder diffraction instrument that Dutch PNAnalytical company dispatches from the factory, Cu target
voltage 40kV, electric current 40mA, sweep limit 5-40 °, scanning step 0.026 °, sweep velocity, acquisition time 12.24s/ walks.
Infrared measurement: the SpectrumTwo type Fourier transform infrared spectrometer adopting perkin elmer, the sample of about 1:100 and KBr mixing are placed in mortar and grind, then put into mould compressing tablet, sweep limit is 400 ~ 4000cm
-1, scanning times is 8.
Differential scanning calorimetric analysis: the Q600 type differential scanning calorimeter adopting U.S. TA, controlling nitrogen protection gas velocity is 50mLmin
-1, sample quality is 5 ~ 10mg, and measuring temperature is 25 ~ 250 DEG C, and heating rate is 10 DEG C of min
-1.
Particle size analysis: adopt Malvern laser particle analyzer model to be Mastersizer3000, based on the particle diameter of volume reference.
The preparation of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N ' used in embodiment 1-4-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate crystal form A (hereinafter referred to as PM crystal form A):
Principal reaction device:
250mL there-necked flask mechanical stirring thermometer spherical condensation tube
Operation steps:
(1) get 10.0gPM-4 (HPLC:93.10%) to be added in 250mL there-necked flask, add 60mL ethanol, stir and be heated to 45 DEG C, dissolving to obtain colourless transparent solution.
(2) 1.8gL-(+)-tartrate is dissolved in 10mL ethanol at 45 DEG C, and is added drop-wise in above-mentioned system, without considerable change.
(3) 45 DEG C of stir about 30min, system gradual change muddiness also separates out solid, in faint yellow suspendible pulpous state.
(4) be cooled to 35 DEG C, stir 1h, then be cooled to-5 DEG C, decompress filter after stirring 1h, the filter cake ethanol rinse of 30mL precooling.This filter cake is dried to constant weight and obtains white solid 9.4g, HPLC:99.78% at 50 DEG C, yield about 86.0%.
(5) get the above-mentioned solid of 9.0g, add 63mL dehydrated alcohol, be heated to 55 DEG C and dissolve completely, lower the temperature after 1h, about 42 DEG C become muddy, and system is gradually in white slurry, and temperature is down to 0-5 DEG C again after being down to 25-30 DEG C and is kept 1-2h, decompress filter, filter cake 25mL0-5 DEG C of dehydrated alcohol drip washing is also dried to constant weight at 50-60 DEG C, obtains 8.1g white solid, HPLC:99.78%, yield about 90.0%, it is 124.0-130.0 DEG C that melting point apparatus surveys fusing point; This prepared crystal is confirmed as PM crystal form A through XRD determining, in embodiment 1-4 below.
Embodiment 1:
Take N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation 0.2039g in mortar, fully grinding 50min is 0.3 μm to particle diameter.Powder after grinding is heated to 145 DEG C with the temperature rise rate of 10 DEG C/min in a nitrogen atmosphere, after stablizing 10min, progressively cools to 15 DEG C, preserve gained solid.Be detected as C crystal form through PXRD, do not detect other crystal formations.
Embodiment 2:
Take N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation 0.1046g in mortar, fully grinding 40min is 0.6 μm to particle diameter.Powder after grinding is heated to 140 DEG C with the temperature rise rate of 20 DEG C/min in a nitrogen atmosphere, after stablizing 20min, progressively cools to room temperature, preserve gained solid.Be detected as C crystal form through PXRD, do not detect other crystal formations.
Embodiment 3:
Take N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation 0.2213g in mortar, fully grinding 60min is 10 μm to particle diameter.Powder after grinding is heated to 150 DEG C with the temperature rise rate of 10 DEG C/min in a nitrogen atmosphere, after stablizing 40min, progressively cools to 30 DEG C, preserve gained solid.Be detected as C crystal form through PXRD, do not detect other crystal formations.
Embodiment 4:
Take N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation 0.2113g in mortar, fully grinding 60min is 3 μm to particle diameter.Powder after grinding is heated to 130 DEG C with the temperature rise rate of 10 DEG C/min in a nitrogen atmosphere, after stablizing 30min, progressively cools to room temperature, preserve gained solid.Be detected as C crystal form through PXRD, do not detect other crystal formations.
Crystal formation qualification test:
X-ray powder diffraction, Infrared spectroscopy and thermal analyses is carried out by N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) the urea tartrate C crystal form product obtained this above-described embodiment 2, determine that the C crystal form prepared belongs to high crystal form purity, other crystal formations do not detected.Specifically, all there is notable difference with the X-ray powder diffraction of raw material used in embodiment 1-3 (all embodiments all adopt identical raw material) A crystal formation at diffraction peak quantity, diffraction peak position, diffraction peak intensity etc. in products C crystal formation; Wherein, as depicted in figs. 1 and 2, Fig. 1 is the X-ray diffraction powder diagram of raw material crystal form A when preparing crystal C; Fig. 2 is the X-ray powder diffractogram that embodiments of the invention 2 obtain crystal C, this crystal C has characteristic diffraction peak as shown in Table 1 below, compared with A crystal formation, the characteristic peak of C crystal form is expressed as 7.3 °, 8.2 °, 12.7 °, 16.0 °, 16.7 °, 18.2 °, 19.3 °, 20.2 °, 23.5 °, 23.9 ° with diffraction angle 2 θ ° ± 0.1.Also there is notable difference in the two infrared spectrum, as shown in Figure 3 and Figure 4, Fig. 3 is the infrared wave spectrogram of raw materials used crystal form A in the embodiment of the present invention, Fig. 4 is the infrared wave spectrogram of crystal C prepared by the embodiment of the present invention 2, find time compared with crystal form A, crystal C has characteristic peak in following chemical shift place: 1542cm
-1, 1426cm
-1, 1329cm
-1, 964cm
-1, 907cm
-1, 881cm
-1, 514cm
-1, 434cm
-1.As shown in Figure 5, the DSC spectrogram of the raw materials used crystal form A of the embodiment of the present invention is shown, as shown in Figure 6, the DSC spectrogram of the crystal C prepared by embodiment 2 is shown, as can be seen from Fig. 5 and Fig. 6, the DSC spectrogram difference of crystal form A and crystal C shows as the fusing point peak of crystal form A at 133 DEG C to 135 DEG C, and the fusing point peak of crystal C is at about 175 DEG C.
The XRD characteristic diffraction peak of crystal C prepared by table 1 embodiment 2 and CN101778821A
(w: weak; Vw: very weak; S: strong; Vs: very strong; M: medium tenacity).
Claims (8)
1. the preparation method of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate crystal C, it is characterized in that, with the A crystal formation of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate for raw material, the method comprises the following steps:
(1) by N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate A crystal formation grinding;
(2) solid after grinding is heated to 130 ~ 150 DEG C under an inert gas; With
(3) crystal C that namely 15-30 DEG C obtain N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate is cooled to.
2. the method for claim 1, is characterized in that, wherein in step (1), described grinding refers to that it is 0.3-10 μm that described A crystal formation is ground to particle size range.
3. method as claimed in claim 1 or 2, is characterized in that, wherein in step (2), keeps 10-40min when being heated to 30 ~ 150 DEG C.
4. method as claimed in claim 1 or 2, is characterized in that, wherein in step (3), be cooled to room temperature and namely obtain described crystal C.
5. the method for claim 1, is characterized in that, in wherein said step (1), 40 ~ 60min is carried out in described grinding.
6. the method as described in any one of claim 1-5, is characterized in that, wherein in step (2), described rare gas element is nitrogen or argon gas.
7. N-(4-luorobenzyl)-N-(1-methyl piperidine-4-the base)-N ' that the preparation method described in any one of claim 1-6 obtains-(4-(2-methyl propoxy-) phenyl methyl) urea tartrate crystal C, it is characterized in that, described crystal C represents to have following characteristic diffraction peak with diffraction angle 2 θ ° ± 0.1: 7.3 °, 8.2 °, 11.9 °, 12.7 °, 13.4 °, 14.3 °, 15.0 °, 16.0 °, 16.7 °, 17.1 °, 18.2 °, 18.8 °, 19.3 °, 20.2 °, 20.7 °, 21.0 °, 21.6 °, 22.5 °, 23.5 °, 23.9 °, 24.6 °, 25.4 °, 26.0 °, 27.4 °, 29.0 ° and 30.4 °.
8. crystal C according to claim 7 is for the preparation of the application in medicine in treatment neuropsychiatric disease, nerve degenerative diseases or dysthymia disorders or somnopathy etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510996797.XA CN105523993A (en) | 2015-12-28 | 2015-12-28 | N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510996797.XA CN105523993A (en) | 2015-12-28 | 2015-12-28 | N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105523993A true CN105523993A (en) | 2016-04-27 |
Family
ID=55766565
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510996797.XA Pending CN105523993A (en) | 2015-12-28 | 2015-12-28 | N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105523993A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018049836A1 (en) * | 2016-05-19 | 2018-03-22 | 上海诚妙医药科技有限公司 | New crystalline form of pimavanserin tartrate, preparation method therefor, and use |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001066521A1 (en) * | 2000-03-06 | 2001-09-13 | Acadia Pharmaceuticals, Inc. | Azacyclic compounds for use in the treatment of serotonin related diseases |
| WO2006036874A1 (en) * | 2004-09-27 | 2006-04-06 | Acadia Pharmaceuticals Inc. | Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation |
| CN1816524A (en) * | 2003-01-16 | 2006-08-09 | 阿卡蒂亚药品公司 | Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases |
| CN101500568A (en) * | 2006-05-15 | 2009-08-05 | 阿卡蒂亚药品公司 | Pharmaceutical formulations of pimavanserin |
| CN101778821A (en) * | 2007-05-15 | 2010-07-14 | 阿卡蒂亚药品公司 | Synthesizing of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-yl)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea and tartrate and crystal formation |
| CN104961672A (en) * | 2015-05-20 | 2015-10-07 | 沈阳药科大学 | Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea |
| CN104961671A (en) * | 2014-09-05 | 2015-10-07 | 苏州晶云药物科技有限公司 | Crystal form of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and preparation method thereof |
| CN105111135A (en) * | 2015-09-09 | 2015-12-02 | 安徽省逸欣铭医药科技有限公司 | Preparation method of substituted urea derivative |
-
2015
- 2015-12-28 CN CN201510996797.XA patent/CN105523993A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001066521A1 (en) * | 2000-03-06 | 2001-09-13 | Acadia Pharmaceuticals, Inc. | Azacyclic compounds for use in the treatment of serotonin related diseases |
| CN1816524A (en) * | 2003-01-16 | 2006-08-09 | 阿卡蒂亚药品公司 | Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases |
| WO2006036874A1 (en) * | 2004-09-27 | 2006-04-06 | Acadia Pharmaceuticals Inc. | Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation |
| CN101031548A (en) * | 2004-09-27 | 2007-09-05 | 阿卡蒂亚药品公司 | Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy) phenylmethyl) carbamide and their preparation |
| CN101035759A (en) * | 2004-09-27 | 2007-09-12 | 阿卡蒂亚药品公司 | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
| CN101500568A (en) * | 2006-05-15 | 2009-08-05 | 阿卡蒂亚药品公司 | Pharmaceutical formulations of pimavanserin |
| CN101778821A (en) * | 2007-05-15 | 2010-07-14 | 阿卡蒂亚药品公司 | Synthesizing of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-yl)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea and tartrate and crystal formation |
| CN104961671A (en) * | 2014-09-05 | 2015-10-07 | 苏州晶云药物科技有限公司 | Crystal form of N-(4-fluorobenzyl)-N-(1-methyl piperidine-4-yl)-N'-(4-(2-methylpropanolato)-phenylmethyl)urea hemitartrate and preparation method thereof |
| CN104961672A (en) * | 2015-05-20 | 2015-10-07 | 沈阳药科大学 | Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea |
| CN105111135A (en) * | 2015-09-09 | 2015-12-02 | 安徽省逸欣铭医药科技有限公司 | Preparation method of substituted urea derivative |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018049836A1 (en) * | 2016-05-19 | 2018-03-22 | 上海诚妙医药科技有限公司 | New crystalline form of pimavanserin tartrate, preparation method therefor, and use |
| CN109563036A (en) * | 2016-05-19 | 2019-04-02 | 上海诚妙医药科技有限公司 | The novel crystal forms and its preparation method and application of Mo Fanselin tartrate |
| US10513495B2 (en) | 2016-05-19 | 2019-12-24 | Shanghai Begreat Pharmatech | Polymorph of pimavanserin tartrate and preparation method thereof and use of same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pando et al. | Preparation of pharmaceutical co-crystals through sustainable processes using supercritical carbon dioxide: a review | |
| WO2016184436A1 (en) | New crystal form of lenvatinib methanesulfonate salt and preparation method thereof | |
| Ervasti et al. | Theophylline–nicotinamide cocrystal formation in physical mixture during storage | |
| Limwikrant et al. | Formation mechanism of a new carbamazepine/malonic acid cocrystal polymorph | |
| Chandel et al. | Co-crystalization of aceclofenac and paracetamol and their characterization. | |
| CA2928287A1 (en) | Solid form of axitinib | |
| CN105061420B (en) | A kind of crystal formation of JAK inhibitor and its preparation method and application | |
| Nguyen et al. | Solvent‐Mediated Polymorphic Transformation of α‐Taltirelin by Seeded Crystallization | |
| CN104496955A (en) | Five different crystalline form substances of dihydromyricelin | |
| Zhao et al. | Co‐Crystal of Paracetamol and Trimethylglycine Prepared by a Supercritical CO2 Anti‐Solvent Process | |
| WO2015093456A1 (en) | Silodosin γ-form crystal and method for producing same | |
| CN102408423B (en) | Method for preparing large particle size dasatinib | |
| Hu et al. | Tranilast-matrine co-amorphous system: Strong intermolecular interactions, improved solubility, and physiochemical stability | |
| EP3006430A1 (en) | Novel form of pyrimidinic compound having dibenzylamine structure | |
| CN109548403A (en) | Crystal form of Galunisertib and its preparation method and application | |
| CN105523993A (en) | N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof | |
| Indra et al. | Enhancing the solubility of ketoconazole via pharmaceutical cocrystal | |
| Soto et al. | Solubility and thermodynamic analysis of famotidine polymorphs in pure solvents | |
| CN103833755A (en) | Crystal form B of Apixaban and preparation method thereof | |
| Han et al. | Self-gelation involved in the transformation of resveratrol and piperine from a co-amorphous system into a co-crystal system | |
| CN104987287A (en) | Preparation method for spherical ketoprofen lysine | |
| JP2021525275A (en) | 2,2,2-Trifluoroacetic acid 1- (2,4-dimethylphenyl) -2-[(3-methoxyphenyl) methylene] Hydrazide polymorph and its production method | |
| Xiong et al. | Effects of temperature and solvent on the solid-state transformations of pranlukast during mechanical milling | |
| WO2021000687A1 (en) | Preparation method for crystal form of pac-1 | |
| EP3484471B1 (en) | Method for producing a polymorphic form of 3-[5-amino-4-(3- cyanobenzoyl)-pyrazol-1-yl]-n-cyclopropyl-4-methylbenzamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160427 |
|
| RJ01 | Rejection of invention patent application after publication |