CN110372568A - A kind of crystallization and preparation method thereof of gliclazide intermediate - Google Patents
A kind of crystallization and preparation method thereof of gliclazide intermediate Download PDFInfo
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- CN110372568A CN110372568A CN201910777859.6A CN201910777859A CN110372568A CN 110372568 A CN110372568 A CN 110372568A CN 201910777859 A CN201910777859 A CN 201910777859A CN 110372568 A CN110372568 A CN 110372568A
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- gliclazide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention relates to crystallizations of a kind of pharmaceutical intermediate and preparation method thereof, are specifically related to a kind of crystallization and preparation method thereof of intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride of gliclazide.
Description
Technical field
The present invention relates to crystallization of a kind of pharmaceutical intermediate and preparation method thereof, it is specifically related in a kind of gliclazide
The crystallization and preparation method thereof of mesosome N- amino-3-azabicyclo [3,3,0] octane hydrochloride.
Background technique
Gliclazide (Gliclazide) is second generation sulfonylurea oral hypoglycemic drug, can be effectively reduced blood glucose and change
Kind coagulation function, especially suitable for the adult-onset diabetes patient of various hypotypes, and Small side effects.With China
The increasingly raising of living standards of the people, diabetes are concerned as a kind of rich people's disease, and research hypoglycemic medicine has extremely important
Practical significance.
Japan Patent (publication number: JP05065270, JP06041073), Chinese patent (publication number 101235011), document
The main technique that gliclazide is prepared disclosed in (Tetrahedron 1991.47 (28), 5161-5172) etc. is as follows:
Wherein, N- amino-3-azabicyclo [3,3,0] octane hydrochloride that formula (I) indicates is the weight for preparing gliclazide
Want intermediate.
Chinese patent 200810060128.1 and 200810061421.X, Zhejiang University's master thesis " gliclazide
Synthesis " (Mei Guangming, 2005), document J.Med.and Pharm.Chem.5,819, Japanese Unexamined Patent Publication 6-41073 is reported
The preparation of N- amino-3-azabicyclo [3,3,0] octane hydrochloride that formula (I) indicates.But do not refer to that formula (I) is indicated
The purification of N- amino-3-azabicyclo [3,3,0] octane hydrochloride, purifying, preservation and obtained for next reaction
All there are many difficulties in high-purity gliclazide etc..It is well known that in chemical synthesis process, especially in industrially preparing process
In, the compound as intermediate, which is preferably provided with high-purity or can easily be separated and be refined, becomes a kind of easy to operate
Crystal form.
Summary of the invention
The technical problem to be solved by the present invention is to the N- ammonia in order to overcome existing gliclazide intermediate formula (I) to indicate
Base -3- azabicyclo [3,3,0] octane hydrochloride purity is not high, is unfavorable for industrialized defect, and provides a kind of Ge Lieqi
The Crystal type and preparation method thereof of special mesosome.Crystal form storage stability of the invention is high, easy to operate, stability is good, with high purity；
And preparation method is simple and reliable, save the cost, separation is simple, is suitable for industrial implement.
According to an aspect of the present invention, the present invention provides the N- that a kind of formula of the intermediate of gliclazide (I) is indicated
The crystal form of amino-3-azabicyclo [3,3,0] octane hydrochloride:
It is radiated using Cu-K α, the X-ray powder diffraction of the crystal form has diffraction maximum in the angle position following 2 θ:
10.85, there is main peak at 16.23,23.44,24.22,26.60,32.75 and 44.12.
It is further preferred that the crystal form has X-ray powder diffraction pattern as shown in Figure 1.
It is further preferred that the crystal form has diffraction maximum in the angle position following 2 θ: 10.49,10.85,16.23,
19.56, there is main peak at 20.23,21.58,23.44,24.22,26.60,29.28,29.82,32.75 and 44.12.
According to another aspect of the present invention, this application provides the N- that the formula (I) of above-mentioned gliclazide intermediate indicates
The preparation method of the crystal form of amino-3-azabicyclo [3,3,0] octane hydrochloride comprising following steps:
A) N- amino-3-azabicyclo [3,3,0] the octane hydrochloride crude product for indicating gliclazide intermediate formula (I) is used
Solvent heating stirring；
B) cooling crystallization, filtering；
C) it is dried under reduced pressure, obtains N- amino-3-azabicyclo [3,3,0] octane salt of gliclazide intermediate formula (I) expression
The crystallization of hydrochlorate.
Wherein, solvent described in step a) is selected from the mixed solvent of one of ethyl acetate and acetonitrile and toluene.Wherein
The volume ratio of the volume and toluene of ethyl acetate or acetonitrile is 2: 1~1: 5, preferably 1:1~1:2.Among gliclazide
The weight ratio of body crude product and mixed solvent is 1: 1~1: 10, preferably 1:2~1:5.
Preferably, step a) dissolves in a heated condition, and temperature is 30 DEG C~reflux temperature when heating stirring, preferably flows back
Temperature.
Preferably, in step b), the type of cooling is the cooling of 5 DEG C/h of programs, and crystallization temperature is -20~20 DEG C, when crystallization
Between be 6~24 hours；In some embodiments, crystallization temperature is -10~10 DEG C in step d), and the crystallization time is 12~24 small
When.
Wherein in step c), drying temperature is 30~80 DEG C.
It should be noted that the diffraction spectrogram obtained by crystalline compounds is for spy in X-ray diffraction spectrum (XRD)
Fixed crystal is often characteristic, and wherein the relative intensity of bands of a spectrum may be because of crystallization condition, partial size and other measurement strips
The difference of part and the advantage orientation effect that generates and change.Therefore, the relative intensity of diffraction maximum is not to targeted crystal
It is characteristic, judge whether with known crystal phase simultaneously, it should be noted that the relative position at peak rather than their phase
To intensity.In addition, there may be slight errors for the position at peak, this is in crystallography art for any given crystal
It is well known.For example, the variation of temperature, sample movement or calibration of instrument etc. when due to analyzing sample, the position at peak can be moved
Dynamic, the evaluated error of 2 θ values is about ± 0.2 ° sometimes.Therefore, when determining every kind of crystal structure, it should consider this error
It is interior.Peak position usually is indicated away from d with 2 angles θ or crystal face in XRD spectrum, between the two with simple conversion relation: d=λ/
2sin θ, wherein d represents crystal face away from λ represents the wavelength of incident X-rays, and θ is the angle of diffraction.
N- amino-3-azabicyclo that therefore, in some cases, the gliclazide intermediate formula (I) indicates [3,3,
0] crystal form of octane hydrochloride has a peak at above-mentioned angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Fig. 1.X
Ray powder diffraction main peaks in this article refer in an X-ray powder diffraction pattern relative intensity 20% or more
Peak, for example, relative intensity is 30% or more, 40% or more, 50% or more, 60% or more, 80% or more,
90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
Preferably, N- amino-3-azabicyclo [3,3,0] octane hydrochloric acid that the gliclazide intermediate formula (I) indicates
The TGA map and Fig. 3 of the crystal form of salt are almost the same.The almost the same heat absorption peak referred in two maps of TGA map, such as its
Initial temperature, it is almost the same in experimental error.
Beneficial effect
The crystal form of N- amino-3-azabicyclo [3,3,0] octane hydrochloride of the invention is easy to maintain, crystallinity is high, stablizes
Property is good, with high purity, easy to operate, is particularly suitable for preparing drug gliclazide；And preparation method is simple and reliable, is suitable for industrial real
It applies.
Detailed description of the invention
Gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride shown in 1 formula of Fig. 1 embodiment (I)
X-ray powder diffraction (XRD) figure of crystallization.
Gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride shown in 2 formula of Fig. 2 embodiment (I)
X-ray powder diffraction (XRD) figure of crystallization.
Gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride shown in 1 formula of Fig. 3 embodiment (I)
Thermogravimetry (TGA) figure of crystallization.
Gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride shown in 2 formula of Fig. 4 embodiment (I)
Thermogravimetry (TGA) figure of crystallization.
Specific embodiment
Hereinafter, will be described in detail the present invention.Before doing so, it should be appreciated that in this specification and appended
Claims used in term should not be construed as being limited to general sense and dictionary meanings, and inventor should allowed
On the basis of the appropriate principle for defining term to carry out best interpretations, according to meaning corresponding with technical aspect of the invention and generally
Thought explains.Therefore, description presented herein is not intended to limitation originally merely for the sake of the preferred embodiment for illustrating purpose
The range of invention, it will thus be appreciated that without departing from the spirit and scope of the present invention, it can be obtained by it
His equivalents or improved procedure.Raw materials and reagents of the present invention are commercially available unless otherwise specified.
Acquire instrument and method used in data:
X-ray powder diffraction spectrum (XRD) measures under the following conditions, instrument and its model: D/Max-RA Japan
II X-ray powder diffraction instrument of RigakuXMiniFlex；Ray: monochromatic Cu-Ka rayScanning mode: θ/2
θ, scanning range: 0~40 °, voltage: 30Kv, electric current 15mA；Detection environmental condition: temperature: 23.9 DEG C, humidity: 38.6%.
Thermogravimetric analysis (TGA) measures under the following conditions, instrument and its model: TG 209F3 thermogravimetric analyzer；Scanning speed
Rate: 10 DEG C/min；Scanning range: 30 DEG C~300 DEG C；Protective gas: nitrogen.
Gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product bibliography Japanese Unexamined Patent Publication
Flat 6-41073 preparation.
Embodiment 1
By gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product 10kg (GC purity
95.4%), with ethyl acetate/toluene mixed solvent (1:1V/V) heating stirring of 30kg, flow back 15min, and filtering cools down cold
But to -10 DEG C of crystallization 12h, filtering, 60 ± 5 DEG C of crystal are dried in vacuo, and obtain gliclazide intermediate N amino-3-azabicyclo
The white crystals 8.91kg of [3,3,0] octane hydrochloride, yield 89.1%, GC purity 99.81%.
X-ray diffraction test analysis is passed through in gained crystallization, and test condition is as follows: being surveyed using Bruker D8 ADVANCE instrument
It is fixed, using CuKa 40Kv40mA as light source, 0.02 ° of step-length, scanning speed: 8 °/min, scanning range: 3 °~80 °, room temperature.Powder
X-ray diffraction analysis the results are shown in Table 1 and attached drawing 1；Thermogravimetric analysis TGA is shown in Fig. 2.
The powder x-ray diffraction data that table 1 crystallizes
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | |
| 2θ | 10.85 | 16.23 | 23.44 | 24.22 | 26.60 | 32.75 | 44.12 |
Embodiment 2
By gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product 100kg (GC purity
95.4%), with acetonitrile/toluene mixed solvent (1:1V/V) heating stirring of 300kg, flow back 15min, filtering, cooling down
To -5 DEG C of crystallization 18h, filtering, 70 ± 5 DEG C of crystal vacuum drying, obtain gliclazide intermediate N amino-3-azabicyclo [3,3,
0] the white crystals 84.1kg of octane hydrochloride, yield 84.1%, GC purity 99.61%.
X-ray diffraction test analysis is passed through in gained crystallization, and test condition is as follows: being surveyed using Bruker D8 ADVANCE instrument
It is fixed, using CuKa 40Kv40mA as light source, 0.02 ° of step-length, scanning speed: 8 °/min, scanning range: 3 °~80 °, room temperature.Powder
X-ray diffraction analysis the results are shown in Table 2 and attached drawing 2.
The powder x-ray diffraction data that table 2 crystallizes
| Serial number | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2θ | 10.49 | 10.85 | 16.23 | 19.56 | 20.23 | 21.58 | 23.44 |
| Serial number | 8 | 9 | 10 | 11 | 12 | 13 | |
| 2θ | 24.22 | 26.60 | 29.28 | 29.82 | 32.75 | 44.12 |
Embodiment 3
By gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product 10kg (GC purity
95.4%), with ethyl acetate/toluene mixed solvent (1:2V/V) heating stirring of 40kg, flow back 15min, and filtering cools down cold
But to -5 DEG C of crystallizations for 24 hours, filtering, 60 ± 5 DEG C of crystal vacuum drying, obtain gliclazide intermediate N amino-3-azabicyclo [3,
3,0] the white crystals 8.83kg of octane hydrochloride, yield 88.3%, GC purity 99.37%.
Embodiment 4
By gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product 10kg (GC purity
95.4%), with ethyl acetate/toluene mixed solvent (1:1V/V) heating stirring of 50kg, flow back 20min, and filtering cools down cold
But for 24 hours to 0 DEG C of crystallization, filter, 60 ± 5 DEG C of crystal vacuum drying, obtain gliclazide intermediate N amino-3-azabicyclo [3,
3,0] the white crystals 8.56kg of octane hydrochloride, yield 85.6%, GC purity 99.65%.
Embodiment 5
By gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product 100kg (GC purity
95.4%), with acetonitrile/toluene mixed solvent (1:2V/V) heating stirring of 500kg, flow back 20min, filtering, cooling down
For 24 hours to 0 DEG C of crystallization, filter, 70 ± 5 DEG C of crystal vacuum drying, obtain gliclazide intermediate N amino-3-azabicyclo [3,3,
0] the white crystals 88.6kg of octane hydrochloride, yield 88.6%, GC purity 99.50%.
Embodiment 6
By gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crude product 100kg (GC purity
95.4%), with acetonitrile/toluene mixed solvent (1:2V/V) heating stirring of 400kg, flow back 20min, filtering, cooling down
For 24 hours to 0 DEG C of crystallization, filter, 70 ± 5 DEG C of crystal vacuum drying, obtain gliclazide intermediate N amino-3-azabicyclo [3,3,
0] the white crystals 89.6kg of octane hydrochloride, yield 89.6%, GC purity 99.40%.
Test example 1
Gliclazide intermediate N amino-3-azabicyclo [3,3,0] octane hydrochloride crystallization to being prepared in embodiment 1
Crystal form further investigates storage stability.
It is placed 6 months under conditions of 40 DEG C and relative humidity 75%, investigates the related substance and changes of contents feelings of sample
Condition.Related substance is measured using efficient liquid phase (GC) method, and content uses titration measuring.
GC testing conditions: with HP-5 (30m × 0.32mm, 0.25 μm) for chromatographic column；Initial temperature is 50 DEG C, with per minute
10 DEG C of rate rises to 230 DEG C；Injector temperature is 250 DEG C；Detector temperature is 300 DEG C, H2:40ml/min, Air:
400ml/min, make-up gas 40ml/min；Carrier gas is nitrogen, and flow velocity is 1ml per minute.
Related substance-measuring result (%)
| Holding time (moon) | 0 | 1 | 2 | 3 | 6 |
| Appearance | White crystal | White crystal | White crystal | White crystal | White crystal |
| Purity | 99.61% | 99.60% | 99.60% | 99.51% | 99.50% |
| Crystal form | Such as Fig. 1 | It is constant | It is constant | It is constant | It is constant |
Assay result (%)
| Holding time (moon) | 0 | 1 | 2 | 3 | 6 |
| Content | 100.02 | 100.02 | 99.99 | 99.98 | 99.98 |
Aforementioned stable test result shows the gliclazide intermediate N amino -3- azepine of preparation according to the present invention
Bicyclic [3,3,0] octane hydrochloride Crystal type is investigated 6 months under the conditions of accelerated stability test, equal in relation to substance and content
Without significant change, it is suitble to save.
Claims (9)
1. the crystalline substance of N- amino-3-azabicyclo [3,3,0] octane hydrochloride that a kind of formula (I) of intermediate of gliclazide indicates
Type:
It is radiated using Cu-K α, the X-ray powder diffraction of the crystal form has diffraction maximum in the angle position following 2 θ: 10.85,
16.23, there is main peak at 23.44,24.22,26.60,32.75 and 44.12.
2. the crystal form of the hydrochloride of the intermediate of gliclazide according to claim 1, which is characterized in that the crystal form tool
Just like X-ray powder diffraction pattern shown in FIG. 1.
3. the crystal form of the hydrochloride of the intermediate of gliclazide according to claim 1, which is characterized in that the crystal form exists
2 angle positions θ have diffraction maximum below: 10.49,10.85,16.23,19.56,20.23,21.58,23.44,24.22,
26.60, there is main peak at 29.28,29.82,32.75 and 44.12.
4. the crystal form of the hydrochloride of the intermediate of gliclazide according to claim 1, which is characterized in that the crystal form
TGA map and Fig. 3 are almost the same.
5. one kind is according to claim 1 to the preparation side of the crystal form of the hydrochloride of gliclazide intermediate described in any one of 4
Method comprising following steps:
A) N- amino-3-azabicyclo [3,3,0] octane hydrochloride crude product solvent for indicating gliclazide intermediate formula (I)
Heating stirring；
B) cooling crystallization, filtering；
C) it is dried under reduced pressure, obtains N- amino-3-azabicyclo [3,3,0] octane hydrochloride of gliclazide intermediate formula (I) expression
Crystallization.
6. preparation method according to claim 5, which is characterized in that solvent described in step a) is selected from ethyl acetate and second
The mixed solvent of one of nitrile and toluene.Wherein the volume ratio of the volume and toluene of ethyl acetate or acetonitrile is 2: 1~1:
5, preferably 1:1~1:2.The weight ratio of gliclazide crude intermediate and mixed solvent is 1: 1~1: 10, preferably
1:2~1:5.
7. preparation method according to claim 5, which is characterized in that step a) dissolves in a heated condition, heating stirring
Shi Wendu is 30 DEG C~reflux temperature, preferably reflux temperature.
8. preparation method according to claim 5, which is characterized in that in step b), the type of cooling is 5 DEG C/h of programs
Cooling, crystallization temperature are -20~20 DEG C, and the crystallization time is 6~24 hours；In some embodiments, crystallization temperature in step d)
Degree is -10~10 DEG C, and the crystallization time is 12~24 hours.
9. preparation method according to claim 5, which is characterized in that in step c), drying temperature is 30~80 DEG C.
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Application publication date: 20191025 |