CN105377840A - Salt of diazacycloheptane compound and crystal form and amorphous substance thereof - Google Patents

Salt of diazacycloheptane compound and crystal form and amorphous substance thereof Download PDF

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Publication number
CN105377840A
CN105377840A CN201480032674.8A CN201480032674A CN105377840A CN 105377840 A CN105377840 A CN 105377840A CN 201480032674 A CN201480032674 A CN 201480032674A CN 105377840 A CN105377840 A CN 105377840A
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hydrochlorides
solvent
scholars
crystal formation
hours
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CN105377840B (en
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宋小叶
劳海萍
盛晓霞
盛晓红
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Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd
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Hangzhou Pushai Pharmaceutical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Disclosed are a salt of diazacycloheptane compound and a crystal form and an amorphous substance thereof, which have improved features in the aspects of solubility, stability, dissolution of solid preparations and the like. Also disclosed are methods for preparing the salt and the crystal form and amorphous substance thereof, a pharmaceutical composition thereof and uses of preparing medicaments for treating and preventing neurological and psychiatric disorders and diseases relevant to hypocretin receptors.

Description

Salt of diazacycloheptane compound and crystal form and amorphous substance thereof
The salt and its crystal formation of a kind of diazepan compounds and amorphous article technical field
The present invention relates to pharmaceutical chemistry crystallization technique field.In particular it relates to a kind of diazepan compounds
MK-4305 salt and its crystal formation and amorphous article, further relates to preparation method, its pharmaceutical composition and the purposes as orexin receptor antagonists of the salt and its crystal formation and amorphous article.Background technology
MK-4305 (English name is Suvorexant) is a kind of new orexin of Mo Shadong drugmakers research and development（Hypocretins) receptor antagonist, for treating or preventing, the nerve relevant with orexin receptor and psychiatric disorders and disease , Te Do are the medicines as treatment insomnia class sleep-disorder.MK-4305 is intended to help to maintain clear-headed neurotransmitter in brain by blocking, to promote sleep.III clinical trial phase data displays, compared with placebo, the medicine be used for treat have a sleepless night, to improve insomniac sleep dormancy Victoria hold and sleep occur it is evident in efficacy.The formulation of MK-4305 clinical tests is tablet, 80 milligrams of dosage 10 milligram.
MK-4305 is a kind of diazepan compounds; chemical name is the chloro- 2- of 5- { (5R) -5- methyl -4- [5- methyl -2- (2 Η -1; 2; 3- triazole -2- bases) benzoyl] -1; 4- Diazesuberane -1- bases 1; 3- benzoxazoles, molecular formula is C23H23C1N602;Molecular weight is 450.9;Chemical structural formula is as follows：
Patent document WO2008/069997A1 discloses MK-4305 and its production and use.
Patent document WO2012/148553A1 discloses MK-4305 anhydrous crystal forms I, anhydrous crystal forms II and preparation method thereof, and discloses its X-ray diffractogram（XRD), Differential scanning calorimetry figure（DSC) and13C- solid state nmr wave spectrums（13C-NMR characterize data).Both anhydrous crystal forms are Mutual Variety Relationships, and mutual temperature is 35 ~ 40 °C, and anhydrous crystal forms I is the most stable of crystal formation of thermodynamics at 35 °C, and anhydrous crystal forms II is the most stable of crystal formation of thermodynamics at 40 °C.
The present inventor's research is found：Above-mentioned MK-4305 anhydrous crystal forms I and anhydrous crystal forms II is hydrophobicity, the solubility extreme difference in water, in the pharmaceutical dosage form for not being suitable for having higher intrinsic solubility requirement.In addition, the change characteristic of both anhydrous crystal forms is also to influence the unfavorable factor of formulation development.Therefore, this area stills need the new MK-4305 of exploitation or the crystal formation or amorphous article of its salt. The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide new MK-4305 salt and its crystal formation and amorphous article, and their preparation method, pharmaceutical composition and purposes.
Compared with known MK-4305 and its crystal formation, the MK-4305 salt and its crystal formation that the present invention is provided should have one or more more superior performances with amorphous article, for example：Stability includes well stability of crystal form, thermal stability, chemical stability, mechanical stability, bin stability etc.；Dissolubility is good；Dissolution rate is fast；Crystallinity is high；It is difficult moisture absorption；It is easy to purify and handles；Chemical purity is high；Low-residual solvent；Hypotoxicity；Granule-morphology is good；Suitable preparation machinability such as good fluidity, favourable powder viscosity, tight ness rating and rammability；Improve preparation apparent；Improve bioavilability and drug effect；Extend storage life；It is adapted in terms of the application of preparation novel form, special Do is that have advantage performance in terms of solubility, dissolution velocity, stability of crystal form, bin stability.
According to the purpose of the present invention, the present invention provides MK-4305 hydrochlorides and its crystal formation and dredges hydrochlorate and MK-4305 phosphate, and their preparation method, pharmaceutical composition and purposes with amorphous article, MK-4305.
MK-4305 hydrochlorides are provided according to the present invention of the present invention, its structural formula is as follows：
The actual content that HPLC characterizes MK-4305 free alkalis in display, MK-4305 hydrochlorides is 92.1%, and theoretical content is 92.5%.Testing result shows：The MK-4305 hydrochlorides are MK-4305 and chlorination Hydrogen with about 1:The compound of 1 mol ratio formation.
According to the purpose of the present invention, the present invention provides the preparation method of MK-4305 hydrochlorides, the described method comprises the following steps：It is 1 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1 :2 MK-4305 and mixed in hydrochloric acid are simultaneously reacted, and solvent is removed after the completion of reaction, obtain the MK-4305 hydrochlorides.
Preferably, the solvent is selected from water, ethanol or its mixture.
Preferably, the temperature of the reaction is 10 ~ 50 °C, and the time of the reaction is 1 ~ 24 hour.
Described " removing solvent " can be completed using the ordinary skill in the art, for example, filter, centrifuge or be spin-dried for；Preferably, solvent is removed using the method that is spin-dried for；The method that is spin-dried for is usually to be rotated with the pressure less than atmospheric pressure, and preferably pressure is less than 0.09MPa;It is highly preferred that the temperature for being spin-dried for method is 10 ~ 50 °C.
Preferably, solution hydrochloric acid or hydrochloric acid formed in the solvent is added in the solution or suspension that MK-4305 formed in the solvent.
" hydrochloric acid " is the chlorination Hydrogen the aqueous solution, (percentage by weight of concentration 37%）, from commercially available.The method that initiation material MK-4305 can refer to patent document WO2008069997A1 reaction schemes G descriptions is prepared, and the document is incorporated into the application by way of quoting its full text. The MK-4305 hydrochlorides of the present invention have following beneficial property and application effect：
1. sour sodium is dredged in dodecyl（SDS in the presence of), MK-4305 hydrochlorides more known MK-4305 of solubility in 25 °C of lower water of the invention solubility is high, illustrates the MK-4305 hydrochlorides of the present invention and has more preferable solubilizing effect.
2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochlorides of the present invention has higher dissolution rate and dissolution rate, thus with more preferable bioavilability.
According to the purpose of the present invention, the present invention provides the crystal formation 1 (be referred to as in the present invention " crystal formation Γ) of MK-4305 hydrochlorides; using Cu- Κ α radiation, the crystal formation I has characteristic peak with the Θ of the angle of diffraction 2 X-ray powder diffraction collections represented in following position：6.6 scholars 0.2., 9.4 scholars 0.2.、 11.0±0.2., 12.8 scholars 0.2., 14.1 scholars 0.2.With 0.2 ° of 16.0 scholar.
In a currently preferred embodiment, radiated using Cu-Ka, the crystal formation I has characteristic peak with the Θ of the angle of diffraction 2 X-ray powder diffraction collections represented in following position：6.6 scholars 0.2.、 9.4±0.2., 11.0 scholars 0.2., 12.8 scholars 0.2., 14.1 scholars 0.2., 16.0 scholars 0.2., 17.9 scholars 0.2ο、 18.8±0.2ο, 20.0 scholars 0.2ο, 22.2 scholars 0.2ο, 0.2 ° of 0.2 ° of 25.0 scholar and 26.0 scholars.
In a further preferred embodiment of the invention, radiated using Cu-Ka, the crystal formation I has characteristic peak and its relative intensity with the Θ of the angle of diffraction 2 X-ray powder diffraction collections represented in following position：
The Θ relative intensities % of the angle of diffraction 2
6.6 0.2 ° 31.5 of scholars
9.4 0.2 ° 29.9 of scholars
11.0±0.2° 100.0
12.8 0.2 ° 40.5 of scholars
13.3 0.2 ° 11.7 of scholars
14.1 0.2 ° 31.3 of scholars
16.0 0.2 ° 42.8 of scholars
17.9 0.2 ° 30.9 of scholars
18.3±0.2° 18.0
18.8±0.2° 39.5
20.0 0.2 ° 48.6 of scholar
20.9 0.2 ° 37.0 of scholars
22.2 0.2 ° 59.3 of scholars
24.4 0.2 ° 20.7 of scholars
25.0±0.2° 61.0
26.0 0.2 ° 59.9 of scholars.
Without limitation, a representative instance of the crystal formation I have the FTIR spectrum of crystal formation I described in X-ray powder diffraction as shown in Figure 1 wave number be 1700,1632,1508,1454,1414,1349, 1304th, there is characteristic peak at 1268,1179,1082,1055,951,884,814 and 704 cm.According to the purpose of the present invention, the present invention provides MK-4305 hydrochloride Forms I preparation method, and it comprises the following steps：By MK-4305 hydrochlorides in C4~C6Suspension is formed in ether, loop crystallization is stirred, by the crystal separation of precipitation, dries, obtains the MK-4305 hydrochloride Forms I.
The C4~C6Ether can be ether, ethyl propyl ether, methyl tertiary butyl ether(MTBE), tert amyl methyl ether(TAME), propyl ether, isopropyl ether；Preferably, the C4~C6Ether is selected from ether, isopropyl ether, methyl tertiary butyl ether(MTBE) or its mixture；It is highly preferred that the C4~C6Ether is ether.
Preferably, the operation temperature of the preparation method is room temperature.
Preferably, in the suspension MK-4305 hydrochlorides consumption be operation temperature under its in the C4~C62 ~ 10 times of solubility, more preferably 2 ~ 5 times in ether.
Preferably, the time of the crystallization is 12 ~ 36 hours, more preferably 12 ~ 24 hours.
Preferably, the temperature of the drying is 10 ~ 60 °C, more preferably 10 ~ 40 °C.
Preferably, the time of the drying is 10 ~ 48 hours, more preferably 10 ~ 24 hours.
Above-mentioned crystal formation I preparation method employs the crystallization mode of magma, is by the supersaturated solution of sample（With the presence of undissolved solid）Loop crystallization is stirred, required crystal is obtained.
The MK-4305 hydrochloride Forms I of the present invention has following beneficial property and application effect：
1. sour sodium is dredged in dodecyl（SDS in the presence of), MK-4305 hydrochloride Forms I more known MK-4305 of solubility in 25 °C of lower water of the invention solubility is high, illustrates the MK-4305 hydrochloride Forms I of the present invention and has more preferable solubilizing effect.
2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochloride Forms I of the present invention has higher dissolution rate and dissolution rate, thus with more preferable bioavilability.
3. MK-4305 hydrochloride Forms I of the invention is placed 4 months in room temperature, the drier of relative humidity 10% ~ 90%, and its crystal formation and fusing point are all constant.Illustrate the bin stability that the MK-4305 hydrochloride Forms I of the present invention has had, be conducive to adapting to manufacture, storage, the various environmental conditions of transport, it can preferably resist and as the problems such as the activity substance content caused by the factors such as time, humidity is uneven, purity declines, preparation machinability is reduced, reduce the curative effect downside risk thus brought and security risk during manufacture, storage, transport etc..
According to the purpose of the present invention, the present invention provides the crystal formation 11 (being referred to as in the present invention " crystal formation II ") of MK-4305 hydrochlorides, radiated using Cu- Κ α, the X-ray powder diffraction figure that the crystal formation II is represented with the Θ of the angle of diffraction 2 has characteristic peak at 16.5 ± 0.2 °.
Without limitation, a representative instance of the crystal formation II has X-ray powder diffraction figure as shown in Figure 3.
The FTIR spectrum of the crystal formation II is to have characteristic peak at 1695,1631,1468,1414,1371,1260,1215,1158,1057,952,924,878,810,770 and 695 cm in wave number.
According to the purpose of the present invention, the present invention provides MK-4305 hydrochloride Forms II preparation method, and it comprises the following steps：MK-4305 hydrochlorides are formed into suspension in organic solvent, wherein the organic solvent Selected from c4~c5Ester, c3~c4Ketone, normal heptane or its mixture, stir loop crystallization, by the crystal separation of precipitation, dry, obtain the crystal formation II.
The c4~c5Ester can be ethyl acetate, isopropyl acetate, propyl acetate, ethyl propionate or isopropyl acetoacetic ester；The c3~c4Ketone can be acetone or butanone.
Preferably, the organic solvent is selected from acetone, butanone, ethyl acetate, isopropyl acetate or normal heptane.Preferably, the operation temperature of the preparation method is room temperature.
Preferably, in the suspension consumption of MK-4305 hydrochlorides be under operation temperature its 2 ~ 10 times, more preferably 2 ~ 5 times of solubility in the organic solvent.
Preferably, the time of the crystallization is 12 ~ 36 hours, more preferably 12 ~ 24 hours.
Preferably, the temperature of the drying is 10 ~ 60 °C, more preferably 10 ~ 40 °C.
Preferably, the time of the drying is 10 ~ 48 hours, more preferably 10 ~ 24 hours.
Above-mentioned crystal formation II preparation method employs the crystallization mode of magma, is by the supersaturated solution of sample（With the presence of undissolved solid）Loop crystallization is stirred, required crystal is obtained.
The hydrochloride Form II of MK- 4305 of the present invention have following beneficial property and application effect：
1. sour sodium is dredged in dodecyl（SDS in the presence of), MK-4305 hydrochloride Forms II more known MK-4305 of solubility in 25 °C of lower water of the invention solubility is high, illustrates the MK-4305 hydrochloride Forms II of the present invention and has more preferable solubilizing effect.
2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochloride Forms II of the present invention has higher dissolution rate and dissolution rate, thus with more preferable bioavilability.
3. MK-4305 hydrochloride Forms II of the invention is placed 4 months in room temperature, 10% ~ 90%RH of relative humidity drier, and its crystal formation and fusing point are all constant.Illustrate the bin stability that the MK-4305 hydrochloride Forms II of the present invention has had, be conducive to adapting to manufacture, storage, the various environmental conditions of transport, it can preferably resist and as the problems such as the activity substance content inequality caused by the factors such as time, humidity is hooked, purity declines, preparation machinability is reduced, reduce the curative effect downside risk thus brought and security risk during manufacture, storage, transport etc..
According to the purpose of the present invention, the amorphous article that the present invention provides MK-4305 hydrochlorides (is referred to as " amorphous article " in the present invention：).
Without limitation, a representative instance of the amorphous article has X-ray powder diffraction figure as shown in Figure 5.
The FTIR spectrum of the amorphous article is 1698,1627,1505,1450,1413,1350,1279,1172,1109,1055,961,824,778 and 702cm- in wave number1Place has characteristic peak.
According to the purpose of the present invention, the present invention provides the preparation method of MK-4305 hydrochloride amorphous articles, and it comprises the following steps：MK-4305 hydrochlorides are formed into suspension in a solvent and loop is stirred, wherein the solvent is selected from water, d ~ C4Alcohol or its mixture, by the solid separation of precipitation, dry, obtain the MK-4305 hydrochlorides amorphous article. The wide c of c4Alcohol can be methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol or sec-butyl alcohol.Preferably, the solvent is selected from methanol, ethanol or water.
Preferably, the operation temperature of the preparation method is 10 ~ 30 °C.
Preferably, in the suspension consumption of MK-4305 hydrochlorides be under operation temperature its 2 ~ 10 times, more preferably 2 ~ 5 times of solubility in the solvent.
Preferably, the time for stirring loop is 12 ~ 36 hours, more preferably 12 ~ 24 hours.
Preferably, the temperature of the drying is 10 ~ 60 °C, more preferably 10 ~ 40 °C.
Preferably, the time of the drying is 10 ~ 48 hours, more preferably 10 ~ 24 hours.
The preparation method of above-mentioned amorphous article employs the crystallization mode of mashing, is by the supersaturated solution of sample
(with the presence of undissolved solid）Loop is stirred in a solvent, obtains required amorphous article.
The MK-4305 hydrochloride amorphous articles of the present invention have following beneficial property and application effect：
1. sour sodium is dredged in dodecyl（SDS in the presence of), MK-4305 hydrochlorides amorphous article more known MK-4305 of solubility in 25 °C of lower water of the invention solubility is high, illustrates the MK-4305 hydrochloride amorphous articles of the present invention and has more preferable solubilizing effect.
2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation containing MK-4305 hydrochlorides amorphous article of the present invention has higher dissolution rate and dissolution rate, thus with more preferable bioavilability.
3. MK-4305 hydrochlorides amorphous article of the invention is placed 4 months in room temperature, 10% ~ 90%RH of relative humidity drier, and its XRD spectrum is constant.Illustrate the bin stability that the MK-4305 hydrochloride amorphous articles of the present invention have had, be conducive to adapting to manufacture, storage, the various environmental conditions of transport, it can preferably resist and as the problems such as the activity substance content caused by the factors such as time, humidity is uneven, purity declines, preparation machinability is reduced, reduce the curative effect downside risk thus brought and security risk during manufacture, storage, transport etc..
In the crystal formation I of MK-4305 hydrochlorides of the present invention, crystal formation II, any preparation method of amorphous article：Except no special is indicated, " room temperature " refers to 10 ~ 30 °C of temperature.
Described " stirring loop ", can be completed using the conventional method of this area, stirred loop mode and stirred such as magnetic force loop, machinery stir loop, it is 50 to stir loop speed：1800 revs/min, preferably 300 ~ 900 revs/min." separation ", can be completed using the ordinary skill in the art, such as filtering, centrifugation.The filtering is usually that, at room temperature to carry out suction filtration less than the pressure of atmospheric pressure, preferably pressure is less than 0.09MPa.The concrete operations of the centrifugation are：The sample for being intended to separation is placed in 2 milliliters of centrifuge tubes, is centrifuged with 6000 revs/min of speed, until solid is all sink to centrifugation bottom of the tube.
Alternatively, the crystal formation or amorphous article obtained after " separation " is washed, washing solvent used is preferably identical with solvent used in the preparation method of crystal formation or amorphous article, and the consumption of cleaning solvent is generally 0.3 ~ 1 times of solvent volume used in the preparation method of crystal formation or amorphous article.
" drying ", can be completed using the ordinary skill in the art, such as air drying, forced air drying or be dried under reduced pressure, and drying equipment is fume hood, convection oven or vacuum drying oven；Can be in the case where depressurizing or not depressurizing Carry out, preferably pressure is less than 0.09Mpa.
According to the purpose of the present invention, the present invention provides -4305 and dredges hydrochlorate, and its structural formula is as follows
HPLC characterizes display, and the actual content that MK-4305 dredges MK-4305 free alkalis in hydrochlorate is 90.2%, and theoretical content is 90.0%.Testing result shows：The MK-4305, which dredges hydrochlorate, to be MK-4305 and dredges acid with about 2:The compound of 1 mol ratio formation.
The MK-4305 dredge hydrochlorate FTIR spectrum wave number be 1696,1635,1621,1573,1505,1451,1412,1342,1263,1179,1042,881,822 and 786 cm-1Place has characteristic peak.
According to the purpose of the present invention, the present invention provides the preparation method that MK-4305 dredges hydrochlorate, the described method comprises the following steps：It is 2 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1 :1 MK-4305 and thin acid are mixed and reacted, and solvent is removed after the completion of reaction, are obtained the MK-4305 and are dredged hydrochlorate.
Preferably, the solvent is selected from water, methanol, ethanol or its mixture.
Preferably, the temperature of the reaction is 10 ~ 50 °C, and the time of the reaction is 1 ~ 24 hour.
Preferably, solvent is removed using the method that is spin-dried for；The method that is spin-dried for is usually to be rotated with the pressure less than atmospheric pressure, and preferably pressure is less than 0.09MPa;It is highly preferred that the temperature for being spin-dried for method is 10 ~ 50 °C.
Preferably, by thin acid or dredge the solution that is formed in the solvent of acid and be added in the solution or suspension that MK-4305 formed in the solvent.
Described " dredging acid ", is the aqueous solution for dredging the acid, (percentage by weight of concentration 98%）, from commercially available.
The method that initiation material MK-4305 can refer to patent document WO2008069997A1 reaction schemes G descriptions is prepared, and the document is incorporated into the application by way of quoting its full text.
The MK-4305 of the present invention, which dredges hydrochlorate, has following beneficial property and application effect：
1. sour sodium is dredged in dodecyl（SDS in the presence of), the solubility that MK-4305 of the invention dredges hydrochlorate more known MK-4305 of solubility in 25 °C of lower water is high, illustrates that the MK-4305 of the present invention dredges hydrochlorate and has more preferable solubilizing effect.
2. compared with the solid pharmaceutical preparation containing known MK-4305, the solid pharmaceutical preparation for dredging hydrochlorate containing MK-4305 of the present invention has higher dissolution rate and dissolution rate, thus with more preferable bioavilability.
According to the purpose of the present invention, the present invention provides MK-4305 phosphate, and its structural formula is as follows：
The actual content that HPLC characterizes MK-4305 free alkalis in display, MK-4305 phosphate is 93.2%, and theoretical content is 93.5%.Testing result shows：The MK-4305 phosphate is MK-4305 and phosphoric acid with about 3:The compound of 1 mol ratio formation.
The phosphatic FTIR spectrums of MK-4305 wave number be 1634,1572,1506,1452,1409,1375,1260,1179,990,952,922,881,823 and 726cm-1Place has characteristic peak.
According to the purpose of the present invention, the present invention provides MK-4305 method for production of phosphate salt, the described method comprises the following steps：It is 3 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1 :1 MK-4305 and phosphoric acid is mixed and reacted, and solvent is removed after the completion of reaction, obtains the MK-4305 phosphate；
Preferably, the solvent is selected from water, methanol, ethanol or its mixture.
Preferably, the temperature of the reaction is 10 ~ 50 °C, and the time of the reaction is 1 ~ 24 hour.
Preferably, solvent is removed using the method that is spin-dried for；The method that is spin-dried for is usually to be rotated with the pressure less than atmospheric pressure, and preferably pressure is less than 0.09MPa;It is highly preferred that the temperature for being spin-dried for method is 10 ~ 50 °C.
Preferably, solution phosphoric acid or phosphoric acid formed in the solvent is added in the solution or suspension that MK-4305 formed in the solvent.
" phosphoric acid " is the aqueous solution of the phosphoric acid, (percentage by weight of concentration 85%）, from commercially available.
The method that initiation material MK-4305 can refer to patent document WO2008069997A1 reaction schemes G descriptions is prepared, and the document is incorporated into the application by way of quoting its full text.
The MK-4305 phosphate of the present invention has following beneficial property and application effect：
1. sour sodium is dredged in dodecyl（SDS in the presence of), MK-4305 phosphate more known MK-4305 of solubility in 25 °C of lower water of the invention solubility is high, illustrates the MK-4305 phosphate of the present invention and has more preferable solubilizing effect.
2. compared with the solid pharmaceutical preparation containing known MK-4305, there is higher dissolution rate and dissolution rate containing the phosphatic solid pharmaceutical preparations of MK-4305 of the present invention, thus with more preferable bioavilability.
According to the purpose of the present invention, the present invention provides a kind of pharmaceutical composition, MK-4305 hydrochloride selected from the present invention of the described pharmaceutical composition comprising treatment and/or prevention effective dose, the amorphous article of crystal formation II, MK-4305 hydrochloride of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 dredge hydrochlorate, MK-4305 phosphate or its combination, and at least one pharmaceutically acceptable carrier or auxiliary agent.In addition, described pharmaceutical composition can also include other pharmaceutically useful MK-4305 or its salt compound, crystal formation or amorphous article.Optionally, described pharmaceutical composition can also be comprising one or more other pharmaceutically useful active constituents of medicine, such as sedative, hypnotic, anxiolytic, antipsychotic drug, other orexin receptor antagonists.
Described pharmaceutical composition can be solid-state, semisolid or liquid, and suitable formulation is prepared into as needed, passes through oral cavity, parenteral（Such as muscle, intraperitoneal, intravenous, ICV, intracranial injection or transfusion, hypodermic injection）, nose, vagina, rectum, the approach such as sublingual, transdermal, local administration.Formulation can be solid dosage forms, for example tablet, capsule, granule, powder and pill；Liquid dosage form, such as solution, syrup, supensoid agent, dispersant and emulsion；Injectable formulation, such as solution, dispersant, suitable for injection before in a liquid Dissolving or suspend it is freeze-dried；Can rectally suppository；Emulsifiable paste, ointment, gel, solution or the suspension that can locally use；The spray of inhalable administration.Formula may be adapted to quick release, sustained release or the regulation release of active component.It can be conventional, dispersible, masticable, Orally dissolving or rapid melting preparation.Described pharmaceutical composition be preferably oral dosage form such as tablet, capsule, granule, powder, pill, more preferably tablet and capsule.
Acceptable carrier or auxiliary agent in described pharmaceutical composition Chinese pharmacology, in the case of solid dosage forms, include but is not limited to：Carrier, including starch or modified starch, sugar such as lactose Xian Victoria elements and its derivative such as powdery Xian Victoria elements, Wei Jing Xian Victoria elements, solid inorganic thing such as calcium phosphate, phosphoric acid Hydrogen calcium, phosphoric acid Hydrogen dicalcium, tricalcium phosphate, hydroxyapatite, thin sour calcium, calcium carbonate, semi-solid such as lipid or paraffin, mannitol, sorbierite etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, Wei Jing Xian Victoria elements, Yi Ji Xian Victoria elements, Qiang Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, Qiang hydroxypropyl methyl Xian Victoria elements, polyethylene glycol, Gong Ju Victoria ketone；Disintegrant, such as starch, sodium carboxymethyl starch, sodium starch glycollate, pregelatinized starch, Jiao Lian Ju Victoria ketone, the plain sodium of Suo Jia Ji Xian Victoria, the plain sodium of Jiao connection Suo Jia Ji Xian Victoria, cataloid, alginic acid；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, talcum, sodium stearyl fumarate, polyethylene glycol；Glidant, such as cataloid, light anhydrous silicic acid, crystallization Xian Victoria elements, talcum powder or magnesium stearate；Complex forming agents, such as various Ji Do cyclodextrin and resin；Rate of release controlling agent, such as Qiang propyl group Xian Victoria elements, Qiang Jia Ji Xian Victoria elements, Qiang hydroxypropyl methyl Xian Victoria elements, Yi Ji Xian Victoria elements, Jia Ji Xian Victoria elements, methyl methacrylate, wax.Other available pharmaceutically acceptable carriers or auxiliary agent include but is not limited to film forming agent, plasticizer, colouring agent, flavor enhancement, viscosity modifier, preservative, antioxidant etc..In oral tablet, commonly utilized carrier includes sugared such as lactose, sucrose, mannitol or sorbierite Xian Victoria cellulose products such as cornstarch, wheaten starch, gelatin, Wei Jing Xian Victoria elements, Qiang hydroxypropyl methyl Xian Victoria elements, the plain sodium of Qiang Jia Ji Xian Victoria and polyvinylpyrrolidone, lubricant such as magnesium stearate, the disintegrant such as plain sodium of cross linked polyvinyl pyrrolidone, Jiao connection Suo Jia Ji Xian Victoria can also be added, tablet core can be further coated, for example, form sugarcoating layer；In oral capsule, useful carrier or auxiliary agent include the plain derivative of lactose, high and low molecular poly, starch, Xian Victoria, magnesium stearate, stearic acid and analog；In the case of oral soft capsule, active constituents of medicine can dissolve or be suspended in suitable liquid, such as fat oil, atoleine or liquid macrogol；In the case of oral administration mixed suspension, active constituents of medicine is mixed with emulsifying agent and suspending agent, sweetener and/or flavor enhancement and/or colouring agent can be added if desired, and MK-4305 hydrochlorides of the invention, the amorphous article of crystal formation II, MK-4305 hydrochloride of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 dredge hydrochlorate or MK-4305 phosphate as active constituents of medicine and be maintained as solid-state form in oral administration mixed suspension.The carrier of each in described pharmaceutical composition or auxiliary agent must be it is acceptable, can be compatible with the other compositions in formula and harmless for sufferer.When preparing pharmaceutical composition, MK-4305 hydrochlorides of the invention, the amorphous article of crystal formation II, MK-4305 hydrochloride of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 dredge hydrochlorate, MK-4305 phosphate or its combination are mixed with one or more pharmaceutically acceptable carriers or auxiliary agent, optionally, are mixed with one or more other drugs active components.Solid pharmaceutical preparation can be prepared by the technique such as directly mixing, pelletizing.Liquid preparation can be prepared by the technique such as dissolving, scattered, emulsification.
According to the purpose of the present invention, the present invention provides the MK-4305 hydrochlorides of the present invention, the crystal formation I of MK-4305 hydrochlorides, the crystal formation II of MK-4305 hydrochlorides, the amorphous article of MK-4305 hydrochlorides, MK-4305 dredges hydrochlorate, the amorphous article or MK-4305 of crystal formation II or the MK-4305 hydrochloride of MK-4305 Gravel hydrochlorates or foregoing crystal formation I or the MK-4305 hydrochloride comprising MK-4305 hydrochlorides of the present invention or MK-4305 hydrochlorides dredge hydrochlorate or MK-4305 phosphate or the pharmaceutical composition of its combination is preparing the purposes in being used to treat and/or prevent the nerve and psychiatric disorders and the medicine of disease relevant with orexin receptor.
According to the purpose of the present invention, the method that the present invention provides treatment and/or the prevention nerve relevant with orexin receptor and psychiatric disorders and disease.In a specific embodiment, the following methods of patient of needs are given：Improve sleep quality；Increase holding property of Shui Mian Victoria；Increase REM sleep；Increase the sleep of 2 phases；Reduce sleep fracture；Treatment insomnia；Improve cognitive；Increase memory retains；Treatment or obesity controlling；Treatment or control are depressed；Treatment, control, improve or Jian Shao Disease epilepsy diseases risk, including Bu Fa Sheng Disease epilepsys；Treatment or control pain, including neuropathic pain；Treatment or control Parkinson's；Treatment or control mental disease；Or treatment, control, improve or reduce schizoid risk, methods described includes giving patient's treatment of needs and/or the MK-4305 hydrochlorides selected from the present invention of prevention effective dose, the crystal formation I of MK-4305 hydrochlorides, the crystal formation Π of MK-4305 hydrochlorides, the amorphous article of MK-4305 hydrochlorides, MK-4305 dredges hydrochlorate, the amorphous article or MK-4305 of crystal formation II or the MK-4305 hydrochloride of MK-4305 Gravel hydrochlorates or foregoing crystal formation I or the MK-4305 hydrochloride comprising MK-4305 hydrochlorides of the present invention or MK-4305 hydrochlorides dredge the pharmaceutical composition of hydrochlorate or MK-4305 Gravel hydrochlorates or its combination.Wherein described patient is mammal including people.Under any circumstance, the active constituents of medicine given should contain sufficient amount of MK-4305, to provide desired therapeutic effect.Selected dosage depends on desired therapeutic effect, and the time is held depending on method of administration and Zhi Liao Victoria.Dosage will be different with patient, and this attribute for depending on disease and the order of severity, the body weight of patient, the specific diet of patient, medicine used at the same time and those skilled in the art will be realized that other factorses.Dosage range is usually about 0.5 milligram to 1.0 grams daily of each patient（With MK-4305 free bases）, optionally, 0.5 milligram to 500 milligrams, optionally, 0.5 milligram to 200 milligrams, optionally, 5 milligrams to 50 milligrams.It can be administered, can be administered for daily 1 to 4 times in the form of single dose or multiple dose, optionally, the administration of 1 time or 2 times be carried out daily.
The foregoing nerve relevant with orexin receptor and psychiatric disorders and disease are in following groups：It is depressed；Anxiety；Habituation；Obsession；Affective disease；Depressibility neuropathy；Dysthymic disorder；Behavioral disorder；Emotionally disturbed；Sexual dysfunction；Sexual psychology dysfunction, sexual disorder；Schizophrenia；Manic depression；Amentia；It is dull-witted；Severe baryencephalia and dyskinesia such as huntington disease and tourette's syndrome；Eating disorder such as apocleisis, bulimia nervosa, cachexia and obesity；Additive feeding behaviour；Carousing defaecation influent pH；Angiocardiopathy；Diabetes；Appetite the sense of taste it is disorderly；Vomiting, nausea；Asthma；Cancer；Parkinson's disease；Cushing's syndrome disease；Basocyte ^ knurls；Prolactinoma；Hyperprolactinemia； Pituitary gland knurl adenoma；Hypothalamic disorder；IBD；Motility disturbances of the stomach；Gastric ulcer;Froehlich's syndromes；Adenohypophysis disease；Pituitary disease；Adenohypophysis deterioration；Adenohypophysis hyperfunction；Hypothalamic adenasthenia；Kallman's syndromes（Anosmia, hyposphresia）；Idiopathic hyperprolactinemia；The inferior colliculus cerebral disorders of growth hormone deficiency；Idiopathic growth is not enough；Nanism；Gigantism；Acromegalia；Biology and day-night rhythm are disorderly；Related with restless leg syndrome to disease such as neurological disorders, neuropathic pain is sleep disordered；Heart and lung diseases, acute and congestive heart failure；Hypopiesia；Hypertension；Urinary retention；Osteoporosis；Angina pectoris；Myocardial infarction；Ischemic or haemorrhagic；Subarachnoid hemorrhage；Ulcer；Allergy；Benign prostatauxe；Chronic renal failure；Nephrosis；Sugared dosis tolerata reduction；Antimigraine；Hyperalgia；Pain；Pain sensitivity such as hyperalgia, causalgia and allodynia improve or exaggeration；Acute Pain；Burn pain；Atypical facial pain；Neuropathic pain；Backache；Complex regional pain syndrome i and II；Arthritic pain；Sports injury pain；The pain such as HIV related to infection;Pain after chemotherapy；Post-stroke pain；Postoperative pain；Neuralgia；Vomiting, nausea；The symptom related to visceral pain such as IBS, and angina；Antimigraine；Bladder incontinence such as urge incontinence；Tolerance to anesthetic or the withdrawal to anesthetic；Sleep-disorder；Narcolepsy；Insomnia；Parasomnia；Jet lag；And the disease that nerve degeneration kind obstacle is included in nosology for example suppresses the compound disease of releasing-dementia-parkinsonism-amyotrophia；Grey ball-ponto-nigral is degenerated；Disease epilepsy diseases；Disease epilepsys are sick and the other diseases related to general orexin system.Brief description of the drawings
Fig. 1 is the crystal formation I of MK-4305 hydrochlorides of the present invention XRPD figures.
Fig. 2 is the crystal formation I of MK-4305 hydrochlorides of the present invention IR figures.
Fig. 3 is the crystal formation II of MK-4305 hydrochlorides of the present invention XRPD figures.
Fig. 4 is the crystal formation II of MK-4305 hydrochlorides of the present invention IR figures.
Fig. 5 is the XRPD figures of the amorphous article of MK-4305 hydrochlorides of the present invention.
Fig. 6 is the IR figures of the amorphous article of MK-4305 hydrochlorides of the present invention.
Fig. 7 is the IR figures that MK-4305 of the present invention dredges hydrochlorate.
Fig. 8 is the phosphatic IR figures of MK-4305 of the present invention.Embodiment
The crystal formation of the present invention, amorphous article and its preparation method and application is described in detail with further reference to following examples, the embodiment in the present invention.It will be apparent for a person skilled in the art that many changes for both material and method can be implemented without departing from the present invention.
Instrument and method used in gathered data：
X-ray powder diffraction（XPRD) ：Used instrument is Bmker D8 Advance diffractometer, copper target wavelength is used for 1.54nm Ka X-rays, in 40kV and 40mA operation Under the conditions of, Θ -2 Θ angular instruments, Mo monochromators, Lynxeye detectors.Instrument is calibrated using preceding with diamond dust.Sample is tested at ambient temperature, and the sample for needing to detect is placed on areflexia plate.Detailed testing conditions are as follows, angular range：40 ° of 2 Θ of 3-, step-length：0.02 ° of 2 Θ, speed：0.2 second/step.
Infrared spectrum analysis（IR) data are picked up from BmkerTensor 27, and instrument control software and DAS are all OPUS, generally use ATR equipment, Ο Ο ^ Ο Ο ^ η-1In the range of gather infrared absorption spectroscopy, the sweep time of sample and blank background is 16 seconds, and instrumental resolution is ^！!!—1。
Nuclear magnetic resonance Hydrogen analysis of spectrums（^HNMR) data are picked up from Bmker Ascend Tm 500.Excited using full range, spectrum width 30PPM, pulse, 30.Angle is excited, and is scanned 16 times, digitized quadrature detection, temperature control 298K.
High-efficient liquid phase analysis（HPLC) data are picked up from Waters2487/2695.Using C18 chromatographic columns, 150mmx4.6mm, 25 °C of column temperature, wavelength 254nm, the ml/min of flow velocity 1.0,80 microlitres of sample size, run time 15 minutes.Solvent is 0.05% trifluoroacetic acid aqueous solution：Acetonitrile=1:1, mobile phase A is 0.05% trifluoroacetic acid aqueous solution, and Mobile phase B is acetonitrile, and gradient is shown in Table 1.
HPLC gradients
Organic element analysis（C, H, N, 0, S) data acquisition is in CE-400, using the burning of horizontal sample introduction, thermal conductivity detector (TCD), sample volume：1 ~ 5 milligram, analysis time：C, H, N are analyzed, less than 5 minutes, scope：LOOppm to 100%.
Various reagents used for example illustrate to be commercially available purchase Wu Te Do in embodiment.
Temperature in embodiment for example illustrates to be room temperature Wu Te Do.
" ultrasound " described in embodiment, can promote sample to dissolve, concrete operations are：The container that will be equipped with sample suspension is placed in ultrasonic cleaner, with 20Khz ~ 40Khz power ultrasonic 1 ~ 60 minute.Ru illustrates Wu Te Do, typically with 40Khz power ultrasonics 5 minutes.
Preparation example 1
MK-4305 free alkalis prepare can according to the wherein used compound of the method described by WO2008/069997A1 reaction schemes G can be according to described by WO2008/069997A1 method prepare.Specially：To 22.3 grams of (5R) -5- methyl isophthalic acids, the hydrochloride of 4- Diazesuberane -1- benzyl formates, 15.9 grams of 2- (2 Η -1,2,3- triazole -2- bases) -5- methyl benzoic acids, 12.8 grams of 1- hydroxyls -7- azacyclo-s BTAs and 43.1 milliliters of N-methylmorpholines are in 300 milliliters of Ν, 22.5 grams of Ν-(3- dimethylaminopropyls) are added in solution in Ν-dimethylformamide, and room temperature will be reacted on stir loop and stay overnight, react water-soluble in ethyl acetate and unsaturated carbonate Hydrogen sodium Distribute, with water, salt water washing, dried with thin sour magnesium between liquid, and concentrated via rotary evaporation, residue is via silica gel chromatography（Ethyl acetate/hexane）, obtain colorless gum (5R) -5- methyl -4- [5- methyl -2- (2 Η -1,2,3-triazoles -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane -1- benzyl formates.
29.6 grams of (5R) -5- methyl -4- [5- methyl -2- (2 Η -1 will be contained; 2; 3- triazole -2- bases) benzoyl] -1; solution of the 4- Diazesuberane -1- benzyl formates in 300 milliliters of ethyl acetate and 200 ml methanols is placed in decompression vacuum pumping in flask, and is purged three times with nitrogen.2.4 gram of 20% Hydrogen palladium oxide on carbon is added into flask.By flask decompression vacuum pumping, and being purged three times with nitrogen again, then swept three times with Hydrogen air-blowings.Reactant is stirred into loop three days under Hydrogen gas atmosphere, is then filtered, filtrate is washed with ethyl acetate, is then washed with methanol by Celite pad.Filtrate is concentrated, white foam (7R) -7- methyl isophthalic acids-[5- methyl -2- (2 Η -1,2,3-triazoles -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane is obtained.
To 21.0 grams of (7R) -7- methyl isophthalic acids-[5- methyl -2- (2 Η -1, 2, 3- triazole -2- bases) benzoyl] -1, 4- Diazesuberanes are in 250 milliliters of Ν, 29.3 milliliters of triethylamines and 13.2 gram 2 are added in solution in Ν-dimethylformamide, 5- bis- chloro- 1, 3- benzoxazoles, and heat mixture 2 hours in 75 °C in oil bath, it is cooled to after room temperature, the reaction is diluted with ethyl acetate, with unsaturated carbonate Hydrogen sodium water solutions, water, salt water washing, dried with thin sour magnesium, after being concentrated via rotary evaporation, residue passes through flash column chromatography（Hexane/ethyl acetate）, obtain gum.The gum stirs loop in the mixture of 150 milliliters of ethyl acetate and 300 milliliters of hexanes and stayed overnight, filtering obtains the chloro- 2- of white solid 5- { (5R) -5- methyl -4- [5- methyl -2- (2 Η -1,2,3- triazole -2- bases) benzoyl] -1,4- Diazesuberane -1- bases } -1,3- benzoxazoles.
1.19 (s, l .7Hz), l .26 (s, l .3Hz), 2.15-2.28 (m, lH), 2.39-2.42 (m, 3H), 3.06-3.10 (m, 1.3Hz), 3.14-3.22 (m, 2H), 3.40-3.53 (m, 2H), 3.56-3.92 (m, 2H), 3.95- 4.25 (m, 2H), 4.55 (d, J=14.4Hz, 0.7Hz), 6.97-7.16 (m, 3H), 7.27-7.36 (m, 2H), 7.69 (s, lH), 7.7 9 (t, J=7.6Hz, lH), 7.92 (d, J=8.0Hz, lH), it is shown as MK-4305.
Embodiment 1
MK-4305 prepared by 1.01 grams of preparation examples 1 is weighed, 50 milliliters of ethanol formation suspension are added；Stir under the conditions of loop, by hydrochloric acid solution（The dissolving with hydrochloric acid of 220 milligrams of concentration 37% is in 10 milliliters of water）It is added dropwise in MK-4305 alcohol suspension, 50 °C are stirred loop 1 hour, 50 °C are spin-dried for removing solvent, and 40 °C are dried in vacuo 10 hours, obtain 1.06 grams of MK-4305 hydrochlorides, yield 97.1%.
HPLC sign displays, MK-4305 and hydrochloric acid are about 1 with mol ratio:1 into MK-4305 hydrochlorides.Elementary analysis：(MK-4305 and hydrochloric acid are using mol ratio as 1 by 56.69%C, 16.74%N, 4.93%H:1 into salt theoretical value：56.63%C, 17.23%N, 4.89%H).
Embodiment 2
MK-4305 prepared by 1.02 grams of preparation examples 1 is weighed, 1200 milliliters of EtOH Sonicate dissolvings are added；Stir under the conditions of loop, by hydrochloric acid solution（The dissolving with hydrochloric acid of 335 milligrams of concentration 37% is in 15 milliliters of ethanol）It is added dropwise in MK-4305 ethanol solution, 30 °C are stirred loop 12 hours, 30 °C are spin-dried for removing solvent, and 25 °C are dried in vacuo 15 hours, obtain 1.05 grams of MK-4305 hydrochlorides, yield 95.2%. HPLC sign displays, MK-4305 and hydrochloric acid are about 1 with mol ratio:1 into MK-4305 hydrochlorides.Elementary analysis：(MK-4305 and hydrochloric acid are using mol ratio as 1 by 56.50%C, 17.14%N, 4.99%H:1 into salt theoretical value：56.63%C, 17.23%N, 4.89%H).
Embodiment 3
MK-4305 prepared by 800 milligrams of preparation examples 1 is weighed, 40 milliliters of ethanol formation suspension are added；Stir under the conditions of loop, by hydrochloric acid solution（The dissolving with hydrochloric acid of 350 milligrams of concentration 37% is in 16 milliliters of water）It is added dropwise in MK-4305 alcohol suspension, 10 °C are stirred loop 24 hours, 10 °C are spin-dried for removing solvent, and 10 °C are dried in vacuo 24 hours, obtain 816 milligrams of MK-4305 hydrochlorides, yield 94.4%.
HPLC sign displays, MK-4305 and hydrochloric acid are about 1 with mol ratio:1 into MK-4305 hydrochlorides.Elementary analysis：(MK-4305 and hydrochloric acid are using mol ratio as 1 by 56.27%C, 16.74%N, 4.97%H:1 into salt theoretical value：56.63%C, 17.23%N, 4.89%H).
The sample and the sample of embodiment 1 of embodiment 2,3 have same or analogous HPLC and elementary analysis result, illustrate that embodiment 2,3 samples and the sample of embodiment 1 are identical materials.
Embodiment 4
500 milligrams of MK-4305 hydrochlorides of the invention are weighed, 50 milliliters of ether formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 30 °C its 2 times of solubility in ether）, this suspension is stirred into loop 12 hours at 30 °C, filtered, filter cake washs with 6 milliliters of ether, 40 °C of dryings 10 hours obtain the crystal formation I of 475 milligrams of MK-4305 hydrochlorides of the invention.
X-ray powder diffraction figure is as shown in Figure 1.Display：The crystal formation I of MK-4305 hydrochlorides.
IR collection of illustrative plates is as shown in Figure 2.
Embodiment 5
750 milligrams of MK-4305 hydrochlorides of the invention are weighed, 50 milliliters of isopropyl ether formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 25 °C its 3 times of solubility in isopropyl ether）, this suspension is stirred into loop 16 hours at 25 °C, filtered, filter cake washs with 10 milliliters of isopropyl ethers, 30 °C of dryings 18 hours obtain the crystal formation I of 698 milligrams of MK-4305 hydrochlorides of the invention.
Embodiment 6
1.25 grams of MK-4305 hydrochlorides of the invention are weighed, 50 milliliters of methyl tertiary butyl ether(MTBE) formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 20 °C its 5 times of solubility in methyl tertiary butyl ether(MTBE)）, this suspension is stirred into loop 24 hours at 20 °C, filtered, filter cake washs with 20 milliliters of methyl tertiary butyl ether(MTBE)s, 10 °C of dryings 24 hours obtain the crystal formation I of 1.12 grams of MK-4305 hydrochlorides of the invention.
Embodiment 7
2.5 grams of MK-4305 hydrochlorides of the invention are weighed, 50 milliliters of ether formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 10 °C its 10 times of solubility in ether）, this suspension is stirred into loop 36 hours at 10 °C, filtered, filter cake washs with 50 milliliters of ether, 60 °C of dryings 48 hours obtain the crystal formation I of 2.17 grams of MK-4305 hydrochlorides of the invention. The sample that embodiment 5 ~ 7 is prepared and the sample of embodiment 4 have same or analogous XRPD collection of illustrative plates and IR collection of illustrative plates（It is not shown）, illustrate that the sample of embodiment 5 ~ 7 and the sample of embodiment 4 are identical crystal formations.Embodiment 8
600 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of acetone formation suspension are added（The consumption of MK-4305 hydrochlorides is 2 times of its solubility in acetone under 30 °C in this suspension）, this suspension is stirred into loop 12 hours at 30 °C, filtered, filter cake washs with 3 milliliters of acetone, 40 °C of dryings 10 hours obtain the crystal formation II of 570 milligrams of MK-4305 hydrochlorides of the invention.
X-ray powder diffraction figure is as shown in Figure 3.Display：The crystal formation II of MK-4305 hydrochlorides.
IR collection of illustrative plates is as shown in Figure 4.
Embodiment 9
900 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of butanone formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 24 °C its 3 times of solubility in butanone）, this suspension is stirred into loop 16 hours at 24 °C, filtered, filter cake washs with 4 milliliters of butanone, 30 °C of dryings 16 hours obtain the crystal formation II of 846 milligrams of MK-4305 hydrochlorides of the invention.
Embodiment 10
Weigh 20 milligrams of MK-4305 hydrochlorides of the invention, add 10 milliliters of ethyl acetate formation suspension (in this suspension the consumption of MK-4305 hydrochlorides be under 18 °C its 5 times of solubility in ethyl acetate）, this suspension is stirred into loop 20 hours at 18 °C, filtered, filter cake washs with 6 milliliters of ethyl acetate, 20 °C of dryings 20 hours obtain the crystal formation II of 18 milligrams of MK-4305 hydrochlorides of the invention.
Embodiment 11
50 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of isopropyl acetate formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 15 °C its 6 times of solubility in isopropyl acetate）, this suspension is stirred into loop 24 hours at 15 °C, filtered, filter cake washs with 8 milliliters of isopropyl acetates, 10 °C of dryings 48 hours obtain the crystal formation II of 44 milligrams of MK-4305 hydrochlorides of the invention.
Embodiment 12
100 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of normal heptane formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 10 °C its 10 times of solubility in normal heptane）, this suspension is stirred into loop 36 hours at 10 °C, filtered, filter cake washs with 10 milliliters of normal heptanes, 60 °C of dryings 24 hours obtain the crystal formation II of 82 milligrams of MK-4305 hydrochlorides of the invention.
The sample that embodiment 9 ~ 12 is prepared and the sample of embodiment 8 have same or analogous XRPD collection of illustrative plates and IR collection of illustrative plates（It is not shown）, illustrate that the sample of embodiment 9 ~ 12 and the sample of embodiment 8 are identical crystal formations.Embodiment 13
800 milligrams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of ethanol formation suspension are added（The consumption of MK-4305 hydrochlorides is 2 times of its solubility in ethanol under 30 °C in this suspension）, this suspension is stirred into loop 12 hours at 30 °C, filtered, filter cake washs with 3 milliliters of ethanol, 40 °C of dryings 10 hours are obtained The amorphous article of 752 milligrams of MK-4305 hydrochlorides of the invention.
X-ray powder diffraction figure is as shown in Figure 5.Display：The amorphous article of MK-4305 hydrochlorides.
IR collection of illustrative plates is as shown in Figure 6.
Embodiment 14
1.2 grams of MK-4305 hydrochlorides of the invention are weighed, 10 ml methanols formation suspension is added（The consumption of MK-4305 hydrochlorides is 3 times of its solubility in methyl alcohol under 26 °C in this suspension）, this suspension is stirred into loop 14 hours at 26 °C, filtered, filter cake washs with 5 ml methanols, 35 °C of dryings 14 hours obtain the amorphous article of 1.1 grams of MK-4305 hydrochlorides of the invention.
Embodiment 15
2 grams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of water formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 20 °C its 5 times of solubility in water）, this suspension is stirred into loop 24 hours at 20 °C, filtered, filter cake is with 7 milliliters of water washings, 10 °C of dryings 48 hours obtain the amorphous article of 1.8 grams of MK-4305 hydrochlorides of the invention.
Embodiment 16
4 grams of MK-4305 hydrochlorides of the invention are weighed, 10 milliliters of sec-butyl alcohol formation suspension are added（In this suspension the consumption of MK-4305 hydrochlorides be under 10 °C its 10 times of solubility in sec-butyl alcohol）, this suspension is stirred into loop 36 hours at 10 °C, filtered, filter cake washs with 10 milliliters of sec-butyl alcohols, 60 °C of dryings 24 hours obtain the amorphous article of 3.4 grams of MK-4305 hydrochlorides of the invention.
The sample that embodiment 14 ~ 16 is prepared has same or analogous XRPD collection of illustrative plates and IR collection of illustrative plates with the sample of embodiment 13（It is not shown）, the sample and the sample of embodiment 13 for illustrating embodiment 14 ~ 16 are identical materials.Embodiment 17
MK-4305 prepared by 900 milligrams of preparation examples 1 is weighed, 30 ml methanols formation suspension is added；Stir under the conditions of loop, by thin acid solution（The thin acid of 100 milligrams of concentration 98% is dissolved in 4 milliliters of water）It is added dropwise in MK-4305 methanol suspension, 30 °C are stirred loop 13 hours, 50 °C are spin-dried for removing solvent, and 40 °C are dried in vacuo 10 hours, obtain 956 milligrams of MK-4305 and dredge hydrochlorate.
HPLC characterizes display, and MK-4305 and thin acid are about 2 with mol ratio:1 dredges hydrochlorate into MK-4305.
IR collection of illustrative plates is as shown in Figure 7.
Embodiment 18
MK-4305 prepared by 1.2 grams of preparation examples 1 is weighed, 100 milliliters of ethanol formation suspension are added；Stir under the conditions of loop, by thin acid solution（The thin acid of 230 milligrams of concentration 98% is dissolved in 13 milliliters of ethanol）It is added dropwise in MK-4305 alcohol suspension, 10 °C are stirred loop 24 hours, 30 °C are spin-dried for removing solvent, and 25 °C are dried in vacuo 15 hours, obtain 1.27 grams of MK-4305 and dredge hydrochlorate.
HPLC characterizes display, and MK-4305 and thin acid are about 2 with mol ratio:1 dredges hydrochlorate into MK-4305.Embodiment 19
MK-4305 prepared by 1.5 grams of preparation examples 1 is weighed, 40 milliliters of n-butanol formation suspension are added；Stir Under the conditions of loop, by thin acid solution（The thin acid of 326 milligrams of concentration 98% is dissolved in 20 milliliters of water）It is added dropwise to
In MK-4305 n-butanol suspension, 50 °C are stirred loop 1 hour, and 10 °C are spin-dried for removing solvent, and 10 °C are dried in vacuo 24 hours, obtain 1.58 grams of MK-4305 and dredge hydrochlorate.
HPLC characterizes display, and MK-4305 and thin acid are about 2 with mol ratio:1 dredges hydrochlorate into MK-4305.The sample and the sample of embodiment 17 of embodiment 18,19 have same or analogous HPLC analyze datas and
IR collection of illustrative plates（It is not shown）, illustrate that embodiment 18,19 samples and the sample of embodiment 17 are identical materials.Embodiment 20
MK-4305 prepared by 620 milligrams of preparation examples 1 is weighed, 50 milliliters of ethanol formation suspension are added；Stir under the conditions of loop, by phosphoric acid solution（The phosphoric acid of 55 milligrams of concentration 85% is dissolved in 10 milliliters of water）It is added dropwise in MK-4305 alcohol suspension, 50 °C are stirred loop 1 hour, 50 °C are spin-dried for removing solvent, and 40 °C are dried in vacuo 10 hours, obtain 635 milligrams of MK-4305 phosphate.
HPLC sign displays, MK-4305 and phosphoric acid are about 3 with mol ratio:1 into MK-4305 phosphate.
IR collection of illustrative plates is as shown in Figure 8.
Embodiment 21
MK-4305 prepared by 1.3 grams of preparation examples 1 is weighed, 1200 milliliters of isopropanol ultrasonic dissolutions are added；Stir under the conditions of loop, by phosphoric acid solution（The phosphoric acid of 160 milligrams of concentration 85% is dissolved in 15 milliliters of isopropanols）It is added dropwise in MK-4305 aqueous isopropanol, 30 °C are stirred loop 12 hours, 30 °C are spin-dried for removing solvent, and 25 °C are dried in vacuo 15 hours, obtain 1.34 grams of MK-4305 phosphate.
HPLC sign displays, MK-4305 and phosphoric acid are about 3 with mol ratio:1 into MK-4305 phosphate.Embodiment 22
MK-4305 prepared by 1.0 grams of preparation examples 1 is weighed, 40 ml methanols formation suspension is added；Stir under the conditions of loop, by phosphoric acid solution（The phosphoric acid of 256 milligrams of concentration 85% is dissolved in 16 milliliters of water）It is added dropwise in MK-4305 methanol suspension, 10 °C are stirred loop 24 hours, 10 °C are spin-dried for removing solvent, and 10 °C are dried in vacuo 24 hours, obtain 1.03 grams of MK-4305 phosphate.
HPLC sign displays, MK-4305 and phosphoric acid are about 3 with mol ratio:1 into MK-4305 phosphate.The sample and the sample of embodiment 20 of embodiment 21,22 have same or analogous HPLC analyze datas and IR collection of illustrative plates（It is not shown）, illustrate that embodiment 21,22 samples and the sample of embodiment 20 are identical materials.Embodiment 23
Tablet（Every contains 10 milligrams of MK-4305) formula is as follows：
The crystal formation I of the MK-4305 hydrochlorides of the present invention：10.8 milligrams
Lactose monohydrate：230.7 milligram
Wei Jing Xian Victoria elements：120.1 milligram
The plain sodium of Jiao connection Suo Jia Ji Xian Victoria：32.0 milligrams
Cataloid：3.2 milligram
Magnesium stearate:3.2 milligram Amount to：400.0 milligram
The preparation process of tablet is as follows：
The crystal formation I of MK-4305 hydrochlorides is mixed with lactose monohydrate using equal increments method and hooked, mixed again with Wei Jing Xian Victoria elements, the plain sodium of Jiao connection Suo Jia Ji Xian Victoria, cataloid, magnesium stearate after hooking, it is placed in tabletting in tablet press machine, adjustment sheet weight, respective tablets are produced, 1000 are prepared altogether.
Embodiment 24
Tablet（Every contains 15 milligrams of MK-4305) formula is as follows：
The crystal formation I of the MK-4305 hydrochlorides of the present invention：16.2 milligrams
Lactose monohydrate：225.3 milligram
Wei Jing Xian Victoria elements：120.1 milligram
The plain sodium of Jiao connection Suo Jia Ji Xian Victoria：32.0 milligrams
Cataloid：3.2 milligram
Magnesium stearate:3.2 milligram
Amount to：400.0 milligram
The preparation process of the tablet is identical with the preparation process of the tablet of embodiment 23.
Embodiment 25
Tablet（Every contains 20 milligrams of MK-4305) formula is as follows：
The crystal formation I of the MK-4305 hydrochlorides of the present invention：21.6 milligrams
Lactose monohydrate：219.9 milligram
Wei Jing Xian Victoria elements：120.1 milligram
The plain sodium of Jiao connection Suo Jia Ji Xian Victoria：32.0 milligrams
Cataloid：3.2 milligram
Magnesium stearate:3.2 milligram
Amount to：400.0 milligram
The preparation process of the tablet is identical with the preparation process of the tablet of embodiment 23.
Embodiment 26-30
Prepare using the MK-4305 hydrochlorides, the amorphous article of crystal formation II, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 of the present invention and dredge hydrochlorate or MK-4305 phosphate as the tablet of active constituents of medicine, specification is that 400 milligrams of , Fen Do of every weight contain 10 milligrams, 15 milligrams, 20 milligrams of MK-4305.
The formula of each tablet is as follows：With reference to the formula of embodiment 23 ~ 25, the crystal formation I Fen Do of MK-4305 hydrochlorides in embodiment 23 ~ 25 MK-4305 hydrochlorides, the amorphous article of crystal formation Π, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 for replacing with the present invention is dredged to identical in the other components and embodiment 23 ~ 25 in hydrochlorate or MK-4305 phosphate, each formula.
The preparation process of each tablet is identical with the preparation process of the tablet of embodiment 23. Embodiment 31
Capsule（Every contains 10 milligrams of MK-4305) formula is as follows：
The crystal formation I of the MK-4305 hydrochlorides of the present invention：10.8 milligrams
Pregelatinized starch：236.2 milligram
Lactose：150.0 milligram
Magnesium stearate：3.0 milligram
Amount to：400.0 milligram
The preparation process of capsule is as follows：
The crystal formation I of MK-4305 hydrochlorides is mixed with pregelatinized starch, lactose, magnesium stearate to be placed in dry granulating machine after hooking and pelletized, obtained dry particl is inputted in capsule filling machine and pours into capsule, corresponding capsule is produced, 1000 is prepared altogether.
Embodiment 32
Capsule（Every contains 15 milligrams of MK-4305) formula is as follows：
The crystal formation I of the MK-4305 hydrochlorides of the present invention：16.2 milligrams
Pregelatinized starch：230.8 milligram
Lactose：150.0 milligram
Magnesium stearate：3.0 milligram
Amount to：400.0 milligram
The preparation process of the capsule is identical with the preparation process of the capsule of embodiment 31.
Embodiment 33
Capsule（Every contains 20 milligrams of MK-4305) formula is as follows：
The crystal formation I of the MK-4305 hydrochlorides of the present invention：21.6 milligrams
Pregelatinized starch：225.4 milligram
Lactose：150.0 milligram
Magnesium stearate：3.0 milligram
Amount to：400.0 milligram
The preparation process of the capsule is identical with the preparation process of the capsule of embodiment 31.
Embodiment 34-38
Prepare using the MK-4305 hydrochlorides, the amorphous article of crystal formation II, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305 of the present invention and dredge hydrochlorate or MK-4305 phosphate as the capsule of active constituents of medicine, specification is that 400 milligrams of , Fen Do of every weight contain 10 milligrams, 15 milligrams, 20 milligrams of MK-4305.
The formula of each capsule is as follows：With reference to the formula of embodiment 31 ~ 33, the crystal formation I Fen Do of MK-4305 hydrochlorides in embodiment 31 ~ 33 MK-4305 hydrochlorides, the amorphous article of crystal formation Π, Μ Κ -4305 hydrochlorides of MK-4305 hydrochlorides, MK-4305 for replacing with the present invention is dredged to identical in the other components and embodiment 31 ~ 33 in hydrochlorate or MK-4305 phosphate, each formula. The preparation process of each capsule is identical with the preparation process of the capsule of embodiment 31.
Embodiment 39
The thin hydrochlorate of MK-4305 hydrochlorides, the amorphous article of crystal formation II, MK-4305 hydrochloride of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305, MK-4305 phosphate to the present invention are compared with MK-4305 free alkalis progress solubility prepared by preparation example 1.
The solubility compares combines HPLC detection methods using neopelex solubilising, and concrete operations are：25 °C of lower Fen Do take 10 milligrams of above-mentioned samples and 100 milligrams of neopelexes, it is placed in 100 milliliters of vials, adds 60 ml deionized waters, 40Khz ultrasound works power ultrasonic 60 minutes, sampling, filtering, filtrate is placed in 5 milliliters of volumetric flasks, is removed after water, use acetonitrile constant volume, HPLC detectable concentrations.It the results are shown in Table 2.
Solubility testing result
It can be seen that by the result of table 2, in 25 °C, water under conditions of addition neopelex, compared with MK-4305, MK-4305 hydrochlorides of the invention, the amorphous article of crystal formation II, MK-4305 hydrochloride of crystal formation I, MK-4305 hydrochloride of MK-4305 hydrochlorides, MK-4305, which dredge hydrochlorate, MK-4305 phosphate, all has solubility in more preferable solubilizing effect and Geng Gao water.Therefore, the amorphous article or MK-4305 of crystal formation II or the MK-4305 hydrochloride of crystal formation I or the MK-4305 hydrochloride of MK-4305 hydrochlorides or MK-4305 hydrochlorides containing the present invention, which dredge hydrochlorate or the phosphatic solid pharmaceutical preparations of MK-4305, can have higher dissolution rate and more preferable bioavilability.Embodiment 40
MK-4305, the MK-4305 hydrochlorides of the present invention, the crystal formation I of the MK-4305 hydrochlorides of the present invention, the crystal formation II of the MK-4305 hydrochlorides of the present invention, the amorphous article of the MK-4305 hydrochlorides of the present invention, the MK-4305 of the present invention for taking preparation example 1 to prepare dredge the MK-4305 phosphate of hydrochlorate and the present invention, tabletting is carried out according to the formula and preparation method of embodiment 23, the comparison of Dissolution of Tablet is then carried out.
With reference to《Chinese Pharmacopoeia》The leaching condition of " Benorilate Tablets " carries out dissolution determination in 2010 editions, and using paddle method, sour sodium is dredged with 900 ml 1% dodecyl（SDS) aqueous solution is as dissolution medium, and 37 °C of temperature stirs loop oar rotating speed for 50 revs/min, a point Do sampled 3ml when 2 minutes, 10 minutes, 20 minutes, 40 minutes, 60 minutes, sour sodium is dredged with 1% dodecyl after every sub-sampling（SDS) aqueous solution is supplied, and HPLC determines each time The concentration of point sample, calculates accumulative dissolution percentage.It the results are shown in Table 3.
The dissolution data of table 3 compare
It can be seen that by the result of table 3, compared with Μ Κ -4305 tablet, Μ Κ -4305 hydrochlorides, the amorphous article of crystal formation II, Μ Κ -4305 hydrochlorides of crystal formation I, Μ Κ -4305 hydrochlorides of Μ Κ -4305 hydrochlorides, the Μ Κ -4305 of the present invention dredges hydrochlorate, the phosphatic tablets of Μ Κ -4305 with higher dissolution rate and faster dissolution rate, thus can have more preferable bioavilability.All patent documents quoted in this specification, it is herein to be incorporated into by way of its full text quoting.The above-mentioned general description of invention and the description to its embodiment to being related in the present invention should not be understood as the limitation constituted to the inventive technique scheme.Those skilled in the art, can be on the premise of without prejudice to involved invention inscape, to above-mentioned general description or/and embodiment according to disclosure of the invention（Including embodiment）In public technology feature increased, reduced or combined, formed and belong to other technical schemes of the invention.The protection domain that protection scope of the present invention should be limited using claims as

Claims (1)

  1. Claim
    1st, structural formula MK-4305 hydrochlorides as follows
    2nd, the preparation method of MK-4305 hydrochlorides described in claim 1, comprises the following steps：It is 1 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1:2 MK-4305 and mixed in hydrochloric acid are simultaneously reacted, and solvent is removed after the completion of reaction, obtain the MK-4305 hydrochlorides；
    Preferably, the solvent is selected from water, ethanol or its mixture；
    Preferably, the temperature of the reaction is 10 ~ 50 °C, and the time of the reaction is 1 ~ 24 hour；Preferably, solvent is removed using the method that is spin-dried for；It is highly preferred that the temperature for being spin-dried for method is 10 ~ 50 °C;Preferably, solution hydrochloric acid or hydrochloric acid formed in the solvent is added in the solution or suspension that MK-4305 formed in the solvent.
    3rd, the crystal formation I of MK-4305 hydrochlorides described in a kind of claim 1, it is characterized in that, radiated using Cu-Ka, the X-ray powder diffraction figure of the crystal formation I is 6.6 ° ± 0.2,9.4 ± 0.2 °, 11.0 ± 0.2 °, 12.8 scholars 0.2 in the Θ of the angle of diffraction 2., 14.1 scholars 0.2.With 16.0 scholars 0.2.Place has characteristic peak.
    4th, according to claim 3 MK-4305 hydrochlorides crystal formation characterized in that, the Μ Κ -4305 crystal formations I X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 0.2 ° of 6.6 scholar, 9.4 scholars 0.2.、 11.0±0.2., 12.8 scholars 0.2.、 14.1±0.2ο, 16.0 scholars 0.2ο, 17.9 scholars 0.2ο、 18.8±0.2ο, 20.0 scholars 0.2ο, 22.2 scholars 0.2ο, 25.0 scholars 0.2.With 26.0 ± 0.2 ° at have characteristic peak.
    5th, according to claim 4 Μ Κ -4305 hydrochlorides crystal formation characterized in that, the Μ Κ -4305 crystal formations I X-ray powder diffraction figure the Θ of the angle of diffraction 2 be following position at there is characteristic peak and its relative intensity：The Θ relative intensities % of the angle of diffraction 2
    6.6 0.2 ° 31.5 of scholars
    9.4 0.2 ° 29.9 of scholars
    11.0±0.2° 100.0
    12.8 0.2 ° 40.5 of scholars
    13.3 0.2 ° 11.7 of scholars
    14.1 0.2 ° 31.3 of scholars
    16.0 0.2 ° 42.8 of scholars
    17.9 0.2 ° 30.9 of scholars
    18.3±0.2° 18.0
    18.8±0.2° 39.5
    20.0 0.2 ° 48.6 of scholars
    20.9 0.2 ° 37.0 of scholars
    22.2 0.2 ° 59.3 of scholars
    24.4 0.2 ° 20.7 of scholars
    25.0±0.2° 61.0
    26.0 0.2 ° 59.9 of scholars
    6th, according to any one of claim 3 ~ 5 MK-4305 hydrochlorides crystal formation I, characterized in that, the FTIR spectrum of the crystal formation I is to have characteristic peak at 1700,1632,1508,1454,1414,1349,1304,1268,1179,1082,1055,951,884,814 and 704 cm in wave number.
    7th, a kind of crystal formation I of MK-4305 hydrochlorides any one of claim 3 ~ 6 preparation method, comprises the following steps：By MK-4305 hydrochlorides in C4~C6Suspension is formed in ether, loop crystallization is stirred, by the crystal separation of precipitation, dries, obtains the crystal formation I of the MK-4305 hydrochlorides；
    Preferably, the C4~C6Ether is selected from ether, isopropyl ether, methyl tertiary butyl ether(MTBE) or its mixture；It is highly preferred that the C4~C6Ether is ether；
    Preferably, the operation temperature of the preparation method is room temperature；
    Preferably, in the suspension MK-4305 hydrochlorides consumption be operation temperature under its in C4~C62 ~ 10 times of solubility, more preferably 2 ~ 5 times in ether；
    Preferably, the time of the crystallization is 12 ~ 36 hours, more preferably 12 ~ 24 hours；
    Preferably, the temperature of the drying is 10 ~ 60 °C, more preferably 10 ~ 40 °C;
    Preferably, the time of the drying is 10 ~ 48 hours, more preferably 10 ~ 24 hours.
    8th, the crystal formation II of MK-4305 hydrochlorides described in a kind of claim 1, it is characterised in that radiated using Cu-Ka, the crystal formation II X-ray powder diffraction figure are to have characteristic peak at 16.5 ± 0.2 ° in the Θ of the angle of diffraction 2.
    9th, the crystal formation II of MK-4305 hydrochlorides according to claim 8, it is characterised in that the MK-4305 crystal formations II has X-ray powder diffraction figure substantially as shown in Figure 3.
    10th, the crystal formation II of MK-4305 hydrochlorides according to claim 8 or claim 9, characterized in that, the FTIR spectrum of the MK-4305 crystal formations II is to have characteristic peak at 1695,1631,1468,1414,1371,1260,1215,1158,1057,952,924,878,810,770 and 695 cm in wave number.
    11st, the crystal formation II of MK-4305 hydrochlorides any one of a kind of claim 8 ~ 10 preparation method, it comprises the following steps：MK-4305 hydrochlorides are formed into suspension in organic solvent, wherein the organic solvent is selected from C4~C5Ester, C3~C4Ketone, normal heptane or its mixture, stir loop crystallization, by the crystal separation of precipitation, dry, obtain the crystal formation Π of the MK-4305 hydrochlorides;
    Preferably, the organic solvent is selected from acetone, butanone, ethyl acetate, isopropyl acetate or normal heptane；Preferably, in the suspension MK-4305 hydrochlorides consumption be operation temperature under its described organic 2 ~ 10 times of solubility, more preferably 2 ~ 5 times in solvent；
    Preferably, the operation temperature of the preparation method is room temperature；
    Preferably, the time of the crystallization is 12 ~ 36 hours, more preferably 12 ~ 24 hours；
    Preferably, the temperature of the drying is 10 ~ 60 °C, more preferably 10 ~ 40 °C;
    Preferably, the time of the drying is 10 ~ 48 hours, more preferably 10 ~ 24 hours.
    12nd, the amorphous article of MK-4305 hydrochlorides described in a kind of claim 1.
    13rd, according to claim 12 MK-4305 hydrochlorides amorphous article, it is characterised in that the MK-4305 amorphous articles have substantially X-ray powder diffraction figure as shown in Figure 5.
    14th, according to claim 12 or 13 MK-4305 hydrochlorides amorphous article, characterized in that, the FTIR spectrum of the MK-4305 amorphous articles is 1698,1627,1505,1450,1413,1350,1279,1172,1109,1055,961,824,778 and 702cm- in wave number1Place has characteristic peak.
    15th, a kind of claim 12：The preparation method of the amorphous article of MK-4305 hydrochlorides any one of 14, it comprises the following steps：MK-4305 hydrochlorides are formed into suspension in a solvent and loop is stirred, wherein the solvent is selected from water, d ~ C4Alcohol or its mixture, by the solid separation of precipitation, dry, obtain the amorphous article of the MK-4305 hydrochlorides；
    Preferably, the solvent is selected from methanol, ethanol or water；
    Preferably, the operation temperature of the preparation method is room temperature；
    Preferably, the time for stirring loop is 12 ~ 36 hours, more preferably 12 ~ 24 hours；
    Preferably, in the suspension consumption of MK-4305 hydrochlorides be under operation temperature its 2 ~ 10 times, more preferably 2 ~ 5 times of solubility in the solvent；
    Preferably, the temperature of the drying is 10 ~ 60 °C, more preferably 10 ~ 40 °C;
    Preferably, the time of the drying is 10 ~ 48 hours, more preferably 10 ~ 24 hours.
    17th, MK-4305 dredges hydrochlorate according to claim 16, characterized in that, the MK-4305 dredge hydrochlorate FTIR spectrum wave number be 1696,1635,1621,1573,1505,1451,1412,1342,1263,1179,1042,881,822 and 786cm-1Place has characteristic peak.
    18th, MK-4305 described in claim 16 or 17 dredges the preparation method of hydrochlorate, comprises the following steps：It is 2 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1 :1 MK-4305 and thin acid are mixed and reacted, and solvent is removed after the completion of reaction, are obtained the MK-4305 and are dredged hydrochlorate；
    Preferably, the solvent is selected from water, methanol, ethanol or its mixture； Preferably, the temperature of the reaction is 10 ~ 50 °C, and the time of the reaction is 1 ~ 24 hour；Preferably, solvent is removed using the method that is spin-dried for；It is highly preferred that the temperature for being spin-dried for method is 10 ~ 50 °C;Preferably, by thin acid or dredge the solution that is formed in the solvent of acid and be added in the solution or suspension that MK-4305 formed in the solvent.
    19th, structure MK-4305 phosphate as follows
    20th, the MK-4305 phosphate according to claim 19, characterized in that, the phosphatic FTIR spectrums of MK-4305 are 1634,1572,1506,1452,1409,1375,1260,1179,990,952,922,881,823 and 726cm- in wave number1Place has characteristic peak.
    21st, MK-4305 method for production of phosphate salt described in claim 19 or 20, comprises the following steps：It is 3 by mol ratio in the solvent selected from water, alcohol or its mixture:1~1 :1 MK-4305 and phosphoric acid is mixed and reacted, and solvent is removed after the completion of reaction, obtains the MK-4305 phosphate；
    Preferably, the solvent is selected from water, methanol, ethanol or its mixture；
    Preferably, the temperature of the reaction is 10 ~ 50 °C, and the time of the reaction is 1 ~ 24 hour；Preferably, solvent is removed using the method that is spin-dried for；It is highly preferred that the temperature for being spin-dried for method is 10 ~ 50 °C;Preferably, solution phosphoric acid or phosphoric acid formed in the solvent is added in the solution or suspension that MK-4305 formed in the solvent.
    22nd, a kind of pharmaceutical composition, its comprising treatment and/or prevention effective dose selected from the crystal formation II of MK-4305 hydrochlorides, claim 12 any one of the crystal formation I of MK-4305 hydrochlorides any one of MK-4305 hydrochlorides described in claim 1, claim 3 ~ 6, claim 8 ~ 10：The amorphous article of MK-4305 hydrochlorides any one of 14, MK-4305 described in claim 16 or 17 dredge MK-4305 phosphoric acid described in hydrochlorate or claim 19 or 20 and at least one pharmaceutically acceptable carrier or auxiliary agent.
    23rd, according to claim 22 described pharmaceutical composition, it is characterised in that described pharmaceutical composition is that oral dosage form includes tablet, capsule, granule, powder and pill；It is highly preferred that described pharmaceutical composition is tablet or capsule.
    24th, MK-4305 hydrochlorides described in claim 1, the crystal formation I of MK-4305 hydrochlorides any one of claim 3 ~ 6, the crystal formation II of MK-4305 hydrochlorides any one of claim 8 ~ 10, claim 12：The amorphous article of MK-4305 hydrochlorides any one of 14, MK-4305 described in claim 16 or 17 dredge hydrochlorate, MK-4305 phosphate described in claim 19 or 20 or the described pharmaceutical composition of claim 22 or 23 are preparing the purposes in being used to treat and/or prevent the nerve and psychiatric disorders and the medicine of disease relevant with orexin receptor；The wherein described nerve relevant with orexin receptor and psychiatric disorders With disease in following groups：It is depressed；Anxiety；Habituation；Obsession；Affective disease；Depressibility neuropathy；Dysthymic disorder；Behavioral disorder；Emotionally disturbed；Sexual dysfunction；Sexual psychology dysfunction, sexual disorder；Schizophrenia；Manic depression；Amentia；It is dull-witted；Severe baryencephalia and dyskinesia such as huntington disease and tourette's syndrome；Eating disorder such as apocleisis, bulimia nervosa, cachexia and obesity；Additive feeding behaviour；Carousing defaecation influent pH；Angiocardiopathy；Diabetes；Appetite the sense of taste it is disorderly；Vomiting, nausea；Asthma；Cancer；Parkinson's disease；Cushing's syndrome disease；Basophilic adenoma；Prolactinoma；Hyperprolactinemia；Pituitary gland knurl adenoma；Hypothalamic disorder；IBD；Motility disturbances of the stomach；Gastric ulcer；Froehlich's syndromes；Adenohypophysis disease；Pituitary disease；Adenohypophysis deterioration；Adenohypophysis hyperfunction；Hypothalamic adenasthenia；Kallman's syndromes；Idiopathic hyperprolactinemia；The inferior colliculus cerebral disorders of growth hormone deficiency；Idiopathic growth is not enough；Nanism；Gigantism；Acromegalia；Biology and day-night rhythm are disorderly；Related with restless leg syndrome to disease such as neurological disorders, neuropathic pain is sleep disordered；Heart and lung diseases, acute and congestive heart failure；Hypopiesia；Hypertension；Urinary retention；Osteoporosis；Angina pectoris；Myocardial infarction；Ischemic or haemorrhagic；Subarachnoid hemorrhage；Ulcer；Allergy；Benign prostatauxe；Chronic renal failure；Nephrosis；Sugared dosis tolerata reduction；Antimigraine；Hyperalgia；Pain；Pain sensitivity such as hyperalgia, causalgia and allodynia improve or exaggeration；Acute Pain；Burn pain；Atypical facial pain；Neuropathic pain；Backache；Complex regional pain syndrome i and II；Arthritic pain；Sports injury pain；The pain such as HIV related to infection;Pain after chemotherapy；Post-stroke pain；Postoperative pain；Neuralgia；Vomiting, nausea；The symptom related to visceral pain such as IBS and angina；Antimigraine；Bladder incontinence such as urge incontinence；Tolerance to anesthetic or the withdrawal to anesthetic；Sleep-disorder；Narcolepsy；Insomnia；Parasomnia；Jet lag；The disease that nerve degeneration kind obstacle is included in nosology for example suppresses releasing-dementia-parkinsonism-amyotrophia and is combined disease；Grey ball-ponto-nigral is degenerated；Disease epilepsy diseases；Disease epilepsys are sick and the other diseases related to general orexin system.
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CN107192766B (en) * 2016-03-14 2022-03-04 广东东阳光药业有限公司 Method for measuring suvorexant chiral isomer by using HPLC
CN109996548A (en) * 2016-12-19 2019-07-09 成药技术Ip控股有限公司 Pharmaceutical formulations of suvorexant
CN110818701A (en) * 2018-08-13 2020-02-21 扬子江药业集团有限公司 Refining method of suvorexant
CN110818701B (en) * 2018-08-13 2023-01-17 扬子江药业集团有限公司 Refining method of suvorexant

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