CN108822054A - Hydrochloric acid Ao Dateluo crystal form C and preparation method thereof - Google Patents
Hydrochloric acid Ao Dateluo crystal form C and preparation method thereof Download PDFInfo
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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Abstract
The present invention relates to a kind of long-acting betas2The crystal form C and preparation method thereof of adrenal gland energy anti-depressant medications hydrochloric acid Ao Dateluo, and the pharmaceutical composition containing the crystal form C, the crystal form is with its X-ray diffractogram characteristic absorption peak characterization.Hydrochloric acid Ao Dateluo crystal form C provided by the invention is not easy the moisture absorption, stability significantly improves compared with prior art, controls convenient for the quality of product；Preparation process is succinct, is conducive to the cost control in industrialized production, economic value with higher.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of crystal form and preparation method thereof of hydrochloric acid Ao Dateluoxin.
Background technique
Hydrochloric acid Ao Dateluo, systematic naming method are：6- hydroxyl -8- (1R) -1- hydroxyl -2- [2- (4- methoxyphenyl) -1,
1- dimethyl ethyl] amino } ethyl } -4H- benzo [1,4] oxazine -3- keto hydrochloride (6-Hydroxy-8- { (1R) -1-
hydroxy-2-{[2-(4-methoxyphenyl)-1,1-dimethyl-ethyl]amino}ethyl}-4H-[1,4]-
Benzoxazin-3-one, hydrochloride), molecular formula:C21H27ClN2O5, molecular weight:386.44 CAS registration number:
868049-49-4, structural formula is as indicated with 1
Hydrochloric acid Ao Dateluo is a kind of long-acting beta2Receptor stimulating agent is suitable for chronic obstructive pulmonary disease (COPD) patient.
It is recorded in the Chinese invention patent application specification of publication number CN101817800A (publication date 2010 on September 1)
6- hydroxyl -8- { 1- hydroxyl -2- { [2- (4- methoxyphenyl) -1,1- dimethyl ethyl] amino } second of enantiomer is not differentiated between
Base } -4H- benzo [1,4] oxazine -3- ketone and its preparation method and application.Publication number CN 102827097A (publication date 2012
December 19) Chinese invention patent application specification disclose pure enantiomter shown in structural formula 1, while disclose as
Under preparation method：
" by 5.25 grams of (17.7 mMs) 6- benzyloxy -8- (R)-Oxyranyle -4H- benzos [1,4] oxazine -3- ketone
It is mixed with 6.30 grams of (35.1 mMs) 2- (4- methoxyl group-phenyl) -1,1- dimethyl-ethylamines with 21 milliliters of isopropanols, and
It is stirred 30 minutes under microwave radiation in 135 DEG C in closed reaction vessel.Solvent is evaporated, and residue is subjected to chromatography
Handle (aluminium oxide；Ethyl acetate/methanol gradient).By the obtained product further by being mixed by diethyl ether/diisopropyl ether
Close the purifying of object recrystallization ", obtain 6- benzyloxy -8- { (R) -1- hydroxyl -2- [2- (4- methoxyl group-phenyl) -1,1- dimethyl-second
Base amino]-ethyl } -4H- benzo [1,4] oxazine -3- ketone.
Then " by 5.33 grams of (11.2 mMs) 6- benzyloxy -8- { (R) -1- hydroxyl -2- [2- (4- methoxyl group-phenyl) -
1,1- dimethyl-ethvlamino]-ethyl } -4H- benzo [suspension and 0.8 of the 1,4] oxazine -3- ketone in 120 ml methanols
The mixing of gram palladium/charcoal (10%), is heated to 50 DEG C, in 3 bars of hydrogen pressure hydrogenations.Then catalyst is filtered, and is evaporated filtrate.It will be residual
Excess is dissolved in 20 milliliters of isopropanols, and 2.5 milliliters of 5 mole hydrochlorides for being dissolved in isopropanol are added.200 milliliters of diethyls of the product
Ether precipitating filters and dry, " obtain 6- hydroxyl -8- { (R) -1- hydroxyl -2- [2- (4- methoxyl group-phenyl) -1,1- diformazan
Base-ethylamino]-ethyl } -4H- benzo [1,4] oxazine -3- ketone-hydrochloride (hydrochloric acid Ao Dateluo).
But inventor's discovery is according to the method described above, hydrochloric acid Ao Dateluo easy to absorb moisture when filtering is changed into grease,
It is unable to get stable crystalline product, very big difficulty is caused to subsequent Quality Control and preparation work.
It is well known that same drug, solubility, stability, mobility, compressibility, biology benefit between different crystal forms
All there may be very big differences for the physicochemical property of the various aspects such as expenditure, to influence the curative effect of drug.Therefore, it is necessary to develop to have
The novel crystal forms of the hydrochloric acid Ao Dateluo of superior physiochemical properties, to be conducive to preparation processing and clinical application.
Summary of the invention
For overcome the deficiencies in the prior art, the present invention provides the crystal form of new hydrochloric acid Ao Dateluo a kind of, and hydrochloric acid Austria reaches
The crystal form C of special sieve.The crystal form is not easy the moisture absorption, and stability significantly improves, and controls convenient for the quality of product；And preparation process letter
It is clean, be conducive to the cost control in industrialized production.
In order to achieve the above-mentioned object of the invention, present invention employs the following technical solutions：
The crystal form C of hydrochloric acid Ao Dateluo shown in structural formula 1 a kind of is indicated wherein being radiated using Cu-K α with 2 θ angles
X ray diffracting spectrum 14.93 ° ± 0.2 °, 19.32 ° ± 0.2 °, 19.76 ° ± 0.2 °, 19.97 ° ± 0.2 °, 22.51 ° ±
There is characteristic absorption peak at 0.2 °, 25.98 ° ± 0.2 °, 29.33 ° ± 0.2 °, 29.61 ° ± 0.2 °, 34.62 ° ± 0.2 °.
Preferably, the crystal form C of the hydrochloric acid Ao Dateluo is radiated using Cu-K α, the X-ray diffractogram indicated with 2 θ angles
Spectrum 12.79 ° ± 0.2 °, 14.93 ° ± 0.2 °, 18.66 ° ± 0.2 °, 19.32 ° ± 0.2 °, 19.76 ° ± 0.2 °, 19.97 ° ±
0.2°、20.88°±0.2°、22.51°±0.2°、24.69°±0.2°、25.98°±0.2°、27.78°±0.2°、28.24°
Have at ± 0.2 °, 29.33 ° ± 0.2 °, 29.61 ° ± 0.2 °, 31.53 ° ± 0.2 °, 34.36 ° ± 0.2 ° and 34.62 ° ± 0.2 °
Characteristic absorption peak.
Preferably, the crystal form C of the hydrochloric acid Ao Dateluo is radiated using Cu-K α, the X-ray diffractogram indicated with 2 θ angles
It composes almost the same with Fig. 1.
It is also an object of the present invention to provide the preparation method of the crystal form C of above-mentioned hydrochloric acid Ao Dateluo, including it is as follows
Step：
I. by hydrochloric acid Ao Dateluo crude product and organic solvent investment reaction vessel, stir, heating makes dissolved clarification, heat preservation after
Continuous stirring；
II. reduce temperature, stir, crystallization, filtering, it is dry to get.
Preferably, the organic solvent is in isopropanol, methanol, ethyl acetate, methylene chloride, toluene and normal propyl alcohol
Two or more.
It is furthermore preferred that the mixed solvent is isopropanol-methanol.
It is furthermore preferred that the volume ratio of isopropanol and methanol is：
Isopropanol：Methanol=7:1~15:1.
Most preferably, the volume ratio of isopropanol and methanol is：
Isopropanol：Methanol=10:1.
Preferably, the w/v of the hydrochloric acid Ao Dateluo crude product and the organic solvent is：
Hydrochloric acid Ao Dateluo crude product：Organic solvent=1g:8ml~1g:15ml；
It is furthermore preferred that the w/v of the hydrochloric acid Ao Dateluo crude product and the organic solvent is：
Hydrochloric acid Ao Dateluo crude product：Organic solvent=1g:13ml.
Preferably, in the step I, 45~50 DEG C, insulated and stirred 20min~1h after dissolved clarification, preferably 0.5h.
Preferably, in the step II, 20~25 DEG C are cooled to, stirs 15-24h, preferably 18h.
Above-mentioned hydrochloric acid Ao Dateluo crude product method can be prepared into described in step 1~3 according to the following examples 1
It arrives.
Third of the present invention is designed to provide a kind of pharmaceutical composition, the crystal form C including above-mentioned hydrochloric acid Ao Dateluo
Or the crystal form C of hydrochloric acid Ao Dateluo that above-mentioned preparation method is prepared, and pharmaceutically acceptable auxiliary material.
Preferably, described pharmaceutical composition is inhalation aerosol, inhalation powder spray or inhalation solution.
In addition, it is also an object of the present invention to provide the crystal form C of above-mentioned hydrochloric acid Ao Dateluo, above-mentioned preparation method system
Purposes of the crystal form C or aforementioned pharmaceutical compositions of standby obtained hydrochloric acid Ao Dateluo in preparation treatment COPD drug.
Hydrochloric acid Ao Dateluo crystal form C provided by the invention, is not easy the moisture absorption, and stability is significantly improved compared with the prior art, is convenient for
The quality of product controls and subsequent preparation processing.The solubility of Ao Dateluo crystal form C prepared by the present invention in water and original
Crystal form is ground compared to significantly improving, drug effect can be increased substantially.Meanwhile the preparation process of the crystal form provided by the invention is succinct,
Be conducive to the cost control in industrialized production, economic value with higher.
Detailed description of the invention
With reference to the accompanying drawing, the present invention is further illustrated.
Fig. 1 is the X diffracting spectrum of hydrochloric acid Ao Dateluo crystal form C prepared by embodiment 1.
Specific embodiment
The present invention is described below with reference to specific embodiments.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, do not limit the scope of the invention in any way.In addition, it should also be understood that, the content lectured herein in reading
Later, those skilled in the art can make various modifications or changes to the present invention, and such equivalent forms equally fall within the application institute
Attached claims limited range.
Experimental method in following embodiments is unless otherwise specified conventional method.Medicine as used in the following examples
Material raw material, reagent material etc. are commercially available products unless otherwise specified.Wherein, portion of reagent, raw material, instrument buy feelings
Condition is as follows：
6- benzyloxy -8- (the chloro--oxazine -3- ketone of 1- hydroxy-ethyl -4H- benzo [Isosorbide-5-Nitrae] of (R) -2-, CAS 869478-
11-5, purity 98% and 2- (4- methoxyl group-phenyl) -1,1- dimethyl-ethyI amine hydrochlorate CAS 56490-93-8, purity
99%, it purchases from Shanghai You Ji Pharmaceutical Technology Co., Ltd.
Nuclear Magnetic Resonance：Bruker AVANCE III HD 500；
Mass spectrograph：LTQ Orbitrap Elite；
Liquid chromatograph：Agilent 1260.
In following embodiments and comparative example, HPLC detection carries out as follows：
Chromatographic column：Waters XBridge 5μm(4.6*250mm)；
Mobile phase：A:0.1% sodium heptanesulfonate (pH3.2) aqueous solution and B:Acetonitrile, gradient elution program are as shown in table 1：
Table 1HPLC gradient elution program
| Time(min) | A% | B% |
| 0 | 73 | 27 |
| 3 | 69 | 27 |
| 23 | 49 | 51 |
| 43 | 35 | 65 |
| 55 | 32 | 68 |
| 55.1 | 73 | 27 |
| 60 | 73 | 27 |
Flow velocity：1.0ml/min；
Column temperature：30℃；
Detection wavelength：220nm；
Sampling volume：10μL；
Test sample dilution：Acetonitrile.
In following embodiment and comparative examples, the testing conditions of X-ray diffraction are：
Instrument model：Bruker D8 Advance
Test condition：X-ray source：Cu-K
Operating current：40mA
Operating voltage：40KV
Detector：PSD
Initial angle：4°(2-θ)
Angle at the end：40°(2-θ)
Increment：0.05°/step
Scanning speed：1sec/step
Embodiment 1The preparation of hydrochloric acid Ao Dateluo crystal form C
1)6- benzyloxy -8- (R)-Oxyranyle -4H- benzo [preparation of 1,4] oxazine -3- ketone
By 100.6g (0.3mol) 6- benzyloxy -8- (chloro- [1,4]-oxazine -3- of 1- hydroxy-ethyl -4H- benzo of (R) -2-
The DMF of ketone and 2L are added into reaction flask, stirring, and ice bath cooling is down to 0 DEG C, are added 2N sodium hydrate aqueous solution 400ml, 0~
5 DEG C insulation reaction four hours, which is poured into ice water, 0~5 DEG C is stirred 1 hour, filtering, and 50 DEG C of vacuum of filter cake are dry
It is dry to obtain the control of 86g off-white powder.Yield 96%, purity HPLC：96.5%.
2)6- benzyloxy -8- { (R) -1- hydroxyl -2- [2- (4- methoxyl group-phenyl) -1,1- dimethyl-ethvlamino]-second Base } [the preparation of 1,4] oxazine -3- ketone of -4H- benzo
Step 1) is prepared 52.5g (0.178mol) 6- benzyloxy -8- (R)-Oxyranyle -4H- benzo [1,
4] oxazine -3- ketone, 63g (0.351mol) 2- (4- methoxyl group-phenyl) -1,1- dimethyl-ethylamine and 500ml isopropanol are added
Into reaction flask, back flow reaction 24 hours, 20~30 DEG C are down to, 30g (0.3mol) concentrated hydrochloric acid, 0~5 DEG C of stirring 1 is then added
Hour, filtering, filter cake is beaten to obtain 60g off-white powder, yield with 500ml anhydrous methanol：66.2%, purity 95.8%
3)The preparation of hydrochloric acid Ao Dateluo crude product
60g (0.117mol) 6- benzyloxy -8- { (R) -1- hydroxyl -2- [2- (4- methoxyl group-that step 2) is prepared
Phenyl) -1,1- dimethyl-ethvlamino]-ethyl } -4H- benzo [Isosorbide-5-Nitrae] oxazine -3- ketone, 600ml methanol and 8g10% palladium carbon
It is added into reaction flask, is heated to 50 DEG C, in 3 bars of hydrogen pressure hydrogenations.Then it filters and removes catalyst, 50 DEG C of vacuum of filtrate are steamed
Dry solvent obtains 49.1g white blister solid, yield：99.27%, purity：95.3%.
4)The preparation of hydrochloric acid Ao Dateluo crystal form C
Hydrochloric acid Ao Dateluo crude product, 50ml isopropanol and 5ml methanol that 5g step 3) is prepared are added to reaction flask
In, stirring is warming up to 45~50 DEG C, dissolved clarification, insulated and stirred half an hour, be cooled to 25 DEG C, 20~25 DEG C insulated and stirred 18 hours,
Filtering, 50 DEG C of filter cake are dried in vacuo to obtain 4.75g off-white powder, yield：95%, purity：99.9%.
1HNMR(DMSO-d6)：δ ppm 1.19 (d, 6H), 2.90 (m, 3H), 3.14 (m, 1H), 3.74 (s, 3H), 4.60
(m, 2H), 5.15 (m, 1H), 6.10 (d, 1H), 6.37 (d, 1H), 6.58 (d, 1H), 6.90 (d, 2H), 7.15 (d, 2H), 8.58
(m, 1H), 8.89 (m, 1H), 9.33 (s, 1H), 10.65 (s, 1H)
MS(ESI)387m/z(M-HCl+H)+。
The X ray diffracting spectrum for the hydrochloric acid Ao Dateluo crystal form C that the present embodiment obtains is as shown in Figure 1, concrete outcome is shown in Table
2。
The X-ray powder diffraction data of 2 hydrochloric acid Ao Dateluo crystal form C of table
| Serial number | Angle | Intensity (%) |
| 1 | 12.79 | 11.3 |
| 2 | 14.93 | 43.3 |
| 3 | 18.66 | 14.2 |
| 4 | 19.32 | 100 |
| 5 | 19.76 | 59.1 |
| 6 | 19.97 | 51.4 |
| 7 | 20.88 | 21.3 |
| 8 | 22.51 | 52.3 |
| 9 | 24.69 | 16.7 |
| 10 | 25.98 | 35.4 |
| 11 | 27.78 | 16.4 |
| 12 | 28.24 | 20.5 |
| 13 | 29.33 | 44.7 |
| 14 | 29.61 | 36.3 |
| 15 | 31.53 | 13.9 |
| 16 | 34.36 | 19.7 |
| 17 | 34.62 | 28.5 |
According to《Chinese Pharmacopoeia》(2005 editions) two annex XIX J drug draws moist test guidelines are tested, and are surveyed
It is moist to determine drawing for the hydrochloric acid Ao Dateluo crystal form C that the present embodiment is prepared, and as a result draws moist weight gain 0.18%.It surveys at room temperature
Fixed, the solubility of crystal C in water is 1050mg/10ml.
Embodiment 2The preparation of hydrochloric acid Ao Dateluo crystal form C
The hydrochloric acid Ao Dateluo crude product that 6g embodiment 1 is obtained, 45ml isopropanol and 3ml methanol are added into reaction flask,
Stirring, is warming up to 45~50 DEG C, makes dissolved clarification, insulated and stirred half an hour, is cooled to 20 DEG C, 20~25 DEG C insulated and stirred 24 hours,
Filtering, 50 DEG C of filter cake are dried in vacuo to obtain 5.4g off-white powder, yield：90%, purity：99.4%.
Using Bruker D8Advance X-ray diffractometer, the product of the present embodiment obtains penetrating with the X that Fig. 1 is almost the same
Ray diffraction diagram composes (map summary).
According to《Chinese Pharmacopoeia》(2005 editions) two annex XIX J drug draws moist test guidelines are tested, and are surveyed
It is moist to determine drawing for the hydrochloric acid Ao Dateluo crystal form C that the present embodiment is prepared, and as a result draws moist weight gain 0.23%.It surveys at room temperature
Fixed, the solubility of crystal C in water is 1050mg/10ml.
Embodiment 3The preparation of hydrochloric acid Ao Dateluo crystal form C
The hydrochloric acid Ao Dateluo crude product that 5.3g embodiment 1 is obtained, 70ml isopropanol and 10ml methanol are added to reaction flask
In, stirring is warming up to 45~50 DEG C, makes dissolved clarification, insulated and stirred half an hour is cooled to 25 DEG C, and 20~25 DEG C of insulated and stirreds 15 are small
When, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 4.8g off-white powder, yield：91%, purity：99.3%.
Using Bruker D8Advance X-ray diffractometer, the product of the present embodiment obtains penetrating with the X that Fig. 1 is almost the same
Ray diffraction diagram composes (map summary).
According to《Chinese Pharmacopoeia》(2005 editions) two annex XIX J drug draws moist test guidelines are tested, and are surveyed
It is moist to determine drawing for the hydrochloric acid Ao Dateluo crystal form C that the present embodiment is prepared, and as a result draws moist weight gain 0.21%.It surveys at room temperature
Fixed, the solubility of crystal C in water is 1050mg/10ml.
Embodiment 4The preparation of hydrochloric acid Ao Dateluo crystal form C
The hydrochloric acid Ao Dateluo crude product that 5g embodiment 1 is obtained, 60ml isopropanol and 5ml ethyl acetate are added to reaction flask
In, stirring is warming up to 45~50 DEG C, makes dissolved clarification, insulated and stirred half an hour is cooled to 20 DEG C, and 20~25 DEG C of insulated and stirreds 18 are small
When, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 4.4g off-white powder, yield：88%, purity：99.2%.Using Bruker D8
Advance X-ray diffractometer, the product of the present embodiment obtain the X ray diffracting spectrum almost the same with Fig. 1 (map summary).
According to《Chinese Pharmacopoeia》(2005 editions) two annex XIX J drug draws moist test guidelines are tested, and are surveyed
It is moist to determine drawing for the hydrochloric acid Ao Dateluo crystal form C that the present embodiment is prepared, and as a result draws moist weight gain 0.29%.It surveys at room temperature
Fixed, the solubility of crystal C in water is 1050mg/10ml.
Embodiment 5The preparation of hydrochloric acid Ao Dateluo crystal form C
The hydrochloric acid Ao Dateluo crude product that 5g embodiment 1 is obtained, 60ml isopropanol and 5ml methylene chloride are added to reaction flask
In, stirring is warming up to 45~50 DEG C, makes dissolved clarification, insulated and stirred half an hour is cooled to 20 DEG C, and 20~25 DEG C of insulated and stirreds 20 are small
When, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 4.5g off-white powder, yield：90%, purity：99.4%.
Using Bruker D8 Advance X-ray diffractometer, the product of the present embodiment obtains the X almost the same with Fig. 1
X ray diffraction map (map summary).
According to《Chinese Pharmacopoeia》(2005 editions) two annex XIX J drug draws moist test guidelines are tested, and are surveyed
It is moist to determine drawing for the hydrochloric acid Ao Dateluo crystal form C that the present embodiment is prepared, and as a result draws moist weight gain 0.28%.It surveys at room temperature
Fixed, the solubility of crystal C in water is 1050mg/10ml.
Comparative example 1The preparation of hydrochloric acid Ao Dateluo
Hydrochloric acid Austria is prepared according to the method (embodiment 1) that the Chinese invention patent application of publication number CN102827097 is recorded
Da Teluo, it is shown that steps are as follows：
By 5.33 grams of (11.2 mMs) 6- benzyloxy -8- { (R) -1- hydroxyl -2- [2- (4- methoxyl group-phenyl) -1,1-
Dimethyl-ethvlamino]-ethyl } -4H- benzo [suspension and 0.8 gram palladium of the 1,4] oxazine -3- ketone in 120 ml methanols/
Charcoal (10%) mixing, is heated to 50 DEG C, in 3 bars of hydrogen pressure hydrogenations.Then catalyst is filtered, and is evaporated filtrate.By residue
It is dissolved in 20 milliliters of isopropanols, and 2.5 milliliters of 5 mole hydrochlorides for being dissolved in isopropanol is added, the product is heavy with 200 milliliters of diethyl ether
It forms sediment, filters and dry.
But when filtering, discovery hydrochloric acid Ao Dateluo easy to absorb moisture is changed into grease, is unable to get stable crystallization
Product.
Comparative example 2The preparation of hydrochloric acid Ao Dateluo
Salt is prepared according to the method that the Chinese invention patent application specification embodiment 1 of publication number CN101208316A is recorded
Sour Ao Dateluo.Yield 63-70%, purity 98.5%.The crystal form of the standby hydrochloric acid Ao Dateluo of the patent system uses Cu-K α spoke
It penetrates, the X ray diffracting spectrum indicated with 2 θ angles is at 11.91 ° ± 0.2 °, 15.19 ° ± 0.2 °, 16.88 ° ± 0.2 °, 17.34 °
±0.2°、19.04°±0.2°、19.71°±0.2°、21.02°±0.2°、21.35°±0.2°、22.15°±0.2°、
There is characteristic absorption peak at 23.21 ° ± 0.2 °, 28.41 ° ± 0.2 °, 29.79 ° ± 0.2 ° and 30.71 ° ± 0.2 °.The crystal room temperature
Under solubility in water be 900mg/10ml.
In short, the present invention provides the novel crystal forms of hydrochloric acid Ao Dateluo a kind of --- hydrochloric acid Ao Dateluo crystal form C, the crystal form
It is not easy the moisture absorption, stability significantly improves, convenient for the quality control of product and subsequent preparation processing.Meanwhile the present invention provides
The crystal form preparation process it is succinct, be conducive to the cost control in industrialized production, economic value with higher.
Claims (9)
1. a kind of crystal form C of hydrochloric acid Ao Dateluo, which is characterized in that the crystal form C of the hydrochloric acid Ao Dateluo uses Cu-K α spoke
It penetrates, the X ray diffracting spectrum indicated with 2 θ angles is at 14.93 ° ± 0.2 °, 19.32 ° ± 0.2 °, 19.76 ° ± 0.2 °, 19.97 °
There is spy at ± 0.2 °, 22.51 ° ± 0.2 °, 25.98 ° ± 0.2 °, 29.33 ° ± 0.2 °, 29.61 ° ± 0.2 °, 34.62 ° ± 0.2 °
Levy absorption peak.
2. the crystal form C of hydrochloric acid Ao Dateluo according to claim 1, which is characterized in that the crystalline substance of the hydrochloric acid Ao Dateluo
Type C is radiated using Cu-K α, the X ray diffracting spectrum indicated with 2 θ angles 12.79 ° ± 0.2 °, 14.93 ° ± 0.2 °,
18.66°±0.2°、19.32°±0.2°、19.76°±0.2°、19.97°±0.2°、20.88°±0.2°、22.51°±
0.2°、24.69°±0.2°、25.98°±0.2°、27.78°±0.2°、28.24°±0.2°、29.33°±0.2°、29.61°
There is characteristic absorption peak at ± 0.2 °, 31.53 ° ± 0.2 °, 34.36 ° ± 0.2 ° and 34.62 ° ± 0.2 °.
3. the crystal form C of hydrochloric acid Ao Dateluo according to claim 2, it is characterised in that：The crystalline substance of the hydrochloric acid Ao Dateluo
Type C is radiated using Cu-K α, and the X ray diffracting spectrum and Fig. 1 indicated with 2 θ angles is almost the same.
4. the preparation method of the crystal form C of hydrochloric acid Ao Dateluo described in any one of claims 1 to 3, includes the following steps：
I. it by hydrochloric acid Ao Dateluo crude product and organic solvent investment reaction vessel, stirs, heating, makes dissolved clarification, heat preservation continues to stir
It mixes；
II. reduce temperature, stir, crystallization, filtering, it is dry to get.
5. the preparation method according to claim 4, which is characterized in that the organic solvent is selected from isopropanol, methanol, second
Two or more in acetoacetic ester, methylene chloride, toluene and normal propyl alcohol；
Preferably, the organic solvent is isopropanol-methanol；It is furthermore preferred that the volume ratio of isopropanol and methanol is：
Isopropanol：Methanol=7:1~15:1, it is furthermore preferred that isopropanol：Methanol=10:1.
6. preparation method according to claim 4 or 5, which is characterized in that the hydrochloric acid Ao Dateluo crude product and described have
The w/v of solvent is：
Hydrochloric acid Ao Dateluo crude product：Organic solvent=1g:8ml~1g:15ml；
Preferably, the w/v of the hydrochloric acid Ao Dateluo crude product and the organic solvent is：
Hydrochloric acid Ao Dateluo crude product：Organic solvent=1g:13ml.
7. the preparation method according to claim 4, which is characterized in that in the step I, be warming up to 45~50 DEG C, dissolved clarification
Insulated and stirred 20min~1h afterwards, preferably 0.5h；In the step II, 20~25 DEG C are cooled to, stirs 15-24h, preferably 18h.
8. a kind of pharmaceutical composition, crystal form C or right including hydrochloric acid Ao Dateluo described in any one of claims 1 to 3
It is required that the crystal form C for the hydrochloric acid Ao Dateluo that preparation method described in any one of 5 to 7 is prepared, and can pharmaceutically receive
Auxiliary material；
Preferably, described pharmaceutical composition is inhalation aerosol, inhalation powder spray or inhalation solution.
9. described in any one of the crystal form C of hydrochloric acid Ao Dateluo described in any one of claims 1 to 3, claim 5 to 7
The crystal form C of hydrochloric acid Ao Dateluo that is prepared of preparation method or pharmaceutical composition according to any one of claims 8 treated in preparation
Purposes in COPD drug.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111380968A (en) * | 2018-12-29 | 2020-07-07 | 天津药业研究院有限公司 | Method for detecting content of odaterol and related substances |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016038628A2 (en) * | 2014-09-09 | 2016-03-17 | Reddy G Pratap | A process for preparing olodaterol and intermediates thereof |
| CN106146425A (en) * | 2004-05-14 | 2016-11-23 | 贝林格尔英格海姆法玛两合公司 | The beta-agonists its preparation method of new enantiomeric pure and the purposes in medicament forms thereof |
| WO2018114887A1 (en) * | 2016-12-20 | 2018-06-28 | Laboratorios Lesvi, S.L. | Improved process for the manufacture of r-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2h-1,4-benzoxazin-3(4h)-one hydrochloride |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146425A (en) * | 2004-05-14 | 2016-11-23 | 贝林格尔英格海姆法玛两合公司 | The beta-agonists its preparation method of new enantiomeric pure and the purposes in medicament forms thereof |
| WO2016038628A2 (en) * | 2014-09-09 | 2016-03-17 | Reddy G Pratap | A process for preparing olodaterol and intermediates thereof |
| WO2018114887A1 (en) * | 2016-12-20 | 2018-06-28 | Laboratorios Lesvi, S.L. | Improved process for the manufacture of r-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2h-1,4-benzoxazin-3(4h)-one hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111380968A (en) * | 2018-12-29 | 2020-07-07 | 天津药业研究院有限公司 | Method for detecting content of odaterol and related substances |
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