CN109970706A - A kind of preparation and refining methd of amber love song Ge Lieting A crystal form - Google Patents
A kind of preparation and refining methd of amber love song Ge Lieting A crystal form Download PDFInfo
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- CN109970706A CN109970706A CN201711447256.7A CN201711447256A CN109970706A CN 109970706 A CN109970706 A CN 109970706A CN 201711447256 A CN201711447256 A CN 201711447256A CN 109970706 A CN109970706 A CN 109970706A
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- lieting
- methyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses the preparations and refining methd of a kind of amber love song Ge Lieting A crystal form, are directly recrystallized in isopropanol/methyl acetate in the mixed solvent with bent Ge Lieting crude free base, obtain bent Ge Lieting free alkali fine work；It is that amber love song Ge Lieting A crystal form is obtained at salt using bent Ge Lieting free alkali fine work and one step of succinic acid at salt solvent with methyl acetate and ethyl alcohol.The method of the invention is easy to operate, and more batches of A crystal forms of trial-production are confirmed through X- powder diffraction, reliable preparation process, favorable reproducibility, is suitble to industrialization expanding production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation of amber love song Ge Lieting A crystal form and purification side
Method.
Background technique
Amber love song Ge Lieting, molecular formula: C22H26FN5O6, Chinese name: 2- (6- (3- amino-piperadine -1- base) -3-
Methyl -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyl) the fluoro- benzonitrile succinate of -4-, trade name: Zafatek,
Its structural formula are as follows:
Amber love song Ge Lieting is a kind of New-type long-acting DPP-IV inhibitor of Japanese military field pharmacy exploitation, the first reality in the whole world
The small molecule diabetes medicament being now administered once a week.The listing in hygienic workfare portion, Japan is obtained on March 26th, 2015
Approval, in China, amber love song Ge Lieting has more registrations so far to be declared, and wherein Shandong pharmacy is in head on April 24th, 2015
Family declares, and belongs to 3 class imitation medicines.
The drug, which is applied for a patent, is related to all various aspects such as synthesis technology, crystal form, crystal form preparation method, is currently known crystal form
For A crystal form, B crystal form, C crystal form, form D, crystal form E, F crystal form, G crystal form and unformed, wherein license protection is A crystal form.
In the A crystal form preparation process for having seen patent literature report, the preparation method that original grinds patent includes: rapid evaporation method, at a slow speed
Evaporation, room temperature paddle method, manufacturing cycle is about 5~7 days, and has been seen in the patent CN102675221 published into salt
Solvent is isopropanol and tetrahydrofuran, uses the biggish two classes solvent of environmental pollution.Therefore, above-mentioned crystal form preparation method is deposited
The defects of getting up in process operations cumbersome, cause serious pollution to the environment, being not suitable with industrialized production requirement.
Summary of the invention
In view of the above existing problems in the prior art, the present invention provides a kind of preparation of amber love song Ge Lieting A crystal form and
Refining methd, this method is easy to operate, and more batches of A crystal forms of trial-production are confirmed through X- powder diffraction, reliable preparation process, favorable reproducibility,
It is suitble to industrialization expanding production.
The preparation and refining methd of a kind of amber love song Ge Lieting A crystal form of the present invention, it is thick with bent Ge Lieting free alkali
Product are directly recrystallized in isopropanol and methyl acetate in the mixed solvent, and bent Ge Lieting free alkali fine work is obtained；With methyl acetate
It is that amber love song Ge Lieting A crystalline substance is obtained at salt using bent Ge Lieting free alkali fine work and one step of succinic acid at salt solvent with ethyl alcohol
Type.
The solvent that the method for the invention uses is the small three classes solvent of environmental pollution, and operational sequence is simple, warp
Powder x-ray diffraction crystal form confirmation, the amber love song Ge Lieting crystal form of this method preparation are preparation patent CN101573351A report
The A type in road is brilliant；The crystal form quality is stablized, and industrialized production requirement is adapted to.
The basic synthetic route that the method for the invention is related to is as follows:
The present invention also provides the preparations and refining methd of a kind of more specifically amber love song Ge Lieting A crystal form, including such as
Lower step:
1) bent Ge Lieting crude product is added to the in the mixed solvent of isopropanol and methyl acetate, is warming up to reflux, after dissolved clarification,
Slow cooling continues stirring 5~20 minutes to 0-20 DEG C, and in this temperature；Precipitating, centrifugal rejection filter, filter cake is through isopropanol and acetic acid
The mixed solvent of methyl esters elutes, and centrifugal rejection filter to no liquid flows out, and obtains bent Ge Lieting fine work；
2) song Ge Lieting fine work is added in methyl acetate, and heating is heated to 30~50 DEG C, and the ethanol solution of succinic acid is delayed
Slow to instill wherein, maintaining reaction temperature is no more than 60 DEG C；It is added dropwise, insulated and stirred 10~60 minutes；Reaction solution is slowly dropped
Temperature continues to stir 1-4h, centrifugal filtration, mixed solvent of the filter cake through methyl acetate and dehydrated alcohol in this temperature to 10-40 DEG C
Elution, centrifugal filtration to no liquid are flowed out, and finished product is obtained.
Further, the weight ratio of isopropanol and methyl acetate in the mixed solvent isopropanol and methyl acetate is in step 1)
4-5:1。
Further, in step 1) slow cooling to 5-10 DEG C.
Further, mixing time is 8-12 minutes in step 1).
Further, the weight percent of succinic acid is 8-12% in the ethanol solution of succinic acid in step 2).
Further, in step 2) the in the mixed solvent methyl acetate and dehydrated alcohol of methyl acetate and dehydrated alcohol weight
Amount is than being 4-5:1.
Further, heating is heated to 40~50 DEG C, preferably 42~48 DEG C in step 2).
Further, maintaining reaction temperature is no more than 48 DEG C in step 2).
Further, insulated and stirred 20-40 minutes in step 2).
Further, in step 2) by reaction solution slow cooling to 20-30 DEG C, in this temperature continue stir 2-2.5h.?
Under this condition, it can further achieve the purpose that purify finished product and improve yield.
The beneficial effects of the present invention are: with patent and amber love song Ge Lieting A crystal form reported in the literature preparation work has been seen
Skill is compared, using to solvent be the small three classes solvent of environmental pollution, A crystal form preparation manipulation process is simple, is easy to carry out
Product is collected, and product purity is high, and crystal form quality is stablized, and carries out providing new mode to be industrial.
Detailed description of the invention
Fig. 1 is amber love song Ge Lieting A crystal form hydrogen spectrum prepared by embodiment 1；
Fig. 2 is amber love song Ge Lieting A crystal form infrared spectroscopy prepared by embodiment 1；
Fig. 3 is the purity analysis of the spit of fland amber love song lattice column A crystal form prepared by embodiment 1；
Fig. 4 is amber love song Ge Lieting A crystal form powder x-ray diffraction prepared by embodiment 1；
Fig. 5 is bent Ge Lieting free alkali single crystal diffraction prepared by embodiment 1；
Fig. 6 is the molecular structure in structure cell prepared by embodiment 1.
Specific embodiment
Unless stated otherwise, the reagent selected in following embodiment is commercially available general reagent.
Embodiment 1
1) it is thick that isopropanol 98g, methyl acetate 23.2g and song Ge Lieting free alkali are added into three mouthfuls of reaction flasks of 500ml
Product 30g, unlatching is warming up to reflux, and after dissolved clarification, slow cooling continues stirring 0.5 hour to 5~10 DEG C, and in this temperature.It takes out
Filter, filter cake are eluted through isopropanol/methyl acetate (w/w 4.26:1) mixed solvent, are filtered, until basic no liquid flows out, obtain song
Ge Lieting wet product.
Bent Ge Lieting wet product is placed in a vacuum drying oven, controls 15~25 DEG C of temperature, is dried in vacuo 2 hours, is warming up to
40~50 DEG C, control 40~50 DEG C of temperature, vacuum degree in -0.06Mpa hereinafter, vacuum drying 12~for 24 hours.Period was every 2 hours
A temperature and vacuum degree are recorded, it is primary every 4 hours stirrings, obtain off-white powder.40~45 DEG C of dryings obtain bent Ge Lieting trip
From alkali fine work, single crystal diffraction map as shown in figure 5, structure in structure cell as shown in fig. 6, wherein Fig. 6 (A) is unit in structure cell
And element number (ball-and-stick model), Fig. 6 (B) are individual molecule structure chart in structure cell.
2) methyl acetate 466g and song Ge Lieting free alkali fine work 25g is added into three mouthfuls of reaction flasks of 1000ml, opens
Stirring is heated to 42~48 DEG C, dissolution clarification.
It is added dropwise to the ethanol solution (dehydrated alcohol 98.9g and succinic acid 9.1g) of succinic acid into solution, maintains reaction temperature
Degree is no more than 48 DEG C.It is added dropwise, insulated and stirred about 0.5h.
By reaction solution slow cooling to 20~30 DEG C, continue 2~2.5h of stirring in this temperature, filters, filter cake is through acetic acid first
The elution of ester/dehydrated alcohol (w/w 4.71:1) mixed solvent, filtering obtain finished product wet product until basic no liquid flows out.
It is dry: amber love song Ge Lieting wet product being placed in a vacuum drying oven, controls 15~25 DEG C of temperature, vacuum drying 2
Hour, be warming up to 40~50 DEG C, control 40~50 DEG C of temperature, vacuum degree in -0.06Mpa hereinafter, vacuum drying 12~for 24 hours.Phase
Between every temperature of 2 hour record and vacuum degree, it is primary every 4 hours stirrings, obtain off-white powder, structural formula is as follows
The physicochemical property of the off-white powder of 2 pairs of embodiment preparations characterizes
1) it is composed as shown in Figure 1 for the nuclear magnetic resonance H of off-white powder prepared by the present invention
This product1H-NMR spectrum integral area, which can be seen that, removes DMSO-d6Residual protons peak (2.503~
2.509ppm) outside with active H (about 8.3~9.8ppm), the non-interactive H atom number phase in 22 H, with target molecule is observed altogether
Symbol.The broad peak of 8.3~9.8ppm of low field area disappears in heavy water displacement hydrogen spectrum, the amido and amber that should be attributed on piperidine ring
Acid at salt 4 active H atoms.
According to chemical shift, 5.106~7.969ppm of low field area has 6 H, is 3 H, 1 H of pyrimidine ring on phenyl ring
Be connected 2 H on methylene with pyrimidine ring；1.376~3.173ppm of high field region has 16 H, is 9 H on piperidine ring, pyrimidine
4 H on 3 H and succinic acid methylene on the connected methyl of ring, are consistent with target molecule.
The peak d at 3.154~3.173ppm and the broad peak at 2.641ppm are two H, H- on 5 methylene1H is related
Spectrum can be seen that same carbon coupling and couple with adjacent 4 H；At multiplet and 1.750~1.760ppm at 1.478~1.502ppm
Multiplet be 2 methylene, two H, influenced to split point by adjacent 1,3 H, and couple with 1,3 H；1.376ppm the width at place
Multiplet at peak and 1.862~1.876ppm is that 3 methylene, two H are coupled with carbon and influenced to split point by adjacent 2,4 H,
And it is coupled with 2,4 H；The broad peak at broad peak and 2.896ppm at 2.688ppm be 1 methylene, two H with carbon coupling and
It is influenced to split point by adjacent 2 H, and is coupled with 2 H；Change of the 4 precedence methyl at 3.090ppm with 3 H on 7 methyl
Coupling association occurs for displacement study overlapping, 4 precedence methyl and 3,3`, 5,5` H；And 3 H on 7 methyl are at 3.090ppm
It is not associated with other H；There there is no and other H unimodal at chemical shift 2.299ppm of 4 H on succinic acid methylene
Coupling association.
The peak ABq at 5.106~5.222ppm is attributed to be connected with pyrimidine ring 8 two H on the methylene of benzyl position,1H-1H
It is observed that being coupled with carbon on Correlated Spectroscopy；Unimodal at 5.392ppm is 6 pyrimidine ring methine H.
It is mutually even that 1 H of 7.336~7.368ppm should be attributed to 9,11 H and ortho position F on 10 hydrogen atoms, with phenyl ring
It closes, and is associated with 9,11 H；The chemical shift of 9 H present in 7.168~7.187ppm, with 10 H on phenyl ring and
Ortho position F is mutually coupled, and forms the peak dd, and be associated with 8,10 H；11 hydrogen atoms are due to by neighbouring strong electron-withdrawing group itrile group
Influence, chemical shift 10 H and meta position F in low field offset, with phenyl ring be mutually coupled, and forms the peak dd, appear in 7.945~
At 7.969ppm, and it is associated with 10 H；
The ownership of above every H according to1H-1H Correlated Spectroscopy can confirm.All hydrogen atoms can be closed on map
The explanation of reason.
2) it is illustrated in figure 2 the infrared analysis of off-white powder prepared by the present invention
Instrument: the 330 type Fourier transform infrared spectrophotometer of AVATAR of U.S. Buddhist nun high-tensile strength company production.
The correction and calibrating of instrument: by the Chinese Pharmacopoeia two annex IV C infrared spectrophotometers of version in 2010 correction and
Calibrating, meets regulation.
Measuring method: KBr pressed disc method
Figure is shown in the infrared Absorption map measurement of this product.Ir data see the table below 1.
The infrared absorption spectrum test data of 1 this product reference substance of table
Parsing: composing from this product IR as it can be seen that succinic acid and amine are at salt in target molecule, primary Ammonium Salt Ionic and hydroxyl its infrared suction
Receipts appear in 3425cm-1In range；The C-H stretching vibration of methyl, methylene appears in 2950cm-1、2934cm-1With
2854cm-1Place；The stretching vibration of itrile group appears in 2225cm-1Place；The stretching vibration absworption peak of carboxylate radical carbonyl appears in
1699cm-1Place；C=O stretching vibration absworption peak on pyrimidine ring appears in 1659cm-1Place；1621cm-1Place is the flexible of double bond
Vibration peak；Fragrant phenyl ring skeletal vibration absorption peak appears in 1586cm-1、1552cm-1、1491cm-1And 1449cm-1Place；1422cm-1、1408cm-1And 1384cm-1Place is then the coupling bands of a spectrum of carboxylate radical；1210cm-1Place is that the stretching vibration of C-F key on phenyl ring is inhaled
Receive peak； 1114cm-1、1084cm-1And 1036cm-1Place is the stretching vibration absworption peak of C-N key；The C-H of trisubstituted benzene ring is bent
Vibration absorption peak appears in 884cm-1、831cm-1And 819cm-1Place.
Conclusion: ir data shows that this product has the basic structure information of amber love song Ge Lieting.Itrile group, carbon fluorine
The characteristic peaks such as key, aromatic rings, carboxylic acid and ammonium ion are obvious.
3) it is illustrated in figure 3 the purity analysis of off-white powder prepared by the present invention, data are as shown in table 2:
The purity analysis of 2 spit of fland amber love song lattice column A manufactured in the present embodiment crystal form of table
Detector A 210nm
| Peak number | Retention time | Area | Area % | Highly | Theoretical cam curve (USP) | Tailing factor | Separating degree (USP) |
| 1 | 2.993 | 49942 | 0.302 | 9001 | 5645 | 1.254 | — |
| 2 | 3.748 | 8762 | 0.053 | 1140 | 4905 | 1.228 | 4.043 |
| 3 | 13.607 | 16490369 | 99.564 | 900586 | 12552 | 1.347 | 28.174 |
| 4 | 16.688 | 7657 | 0.046 | 268 | 13233 | 3.831 | 5.780 |
| 5 | 19.563 | 5851 | 0.035 | 447 | 49604 | 1.506 | 6.172 |
| It amounts to | 16562580 | 100.000 | 911441 |
4) the X-ray diffraction analysis of off-white powder manufactured in the present embodiment, as shown in Figure 4:
Test equipment: X, Pert Pro MPDX- x ray diffractometer x
Test condition: DS=1 ° of 0.02 ° of SS=1 ° of RS=0.3mm step-length；Time constant 0.6s
Test result: powder X-ray diffraction peak data are shown in Table 3.
3 powder X-ray diffraction peak list of table (± 0.2 degree)
* peak intensity can change with crystallite size and form.
It is determined according to the report of crystal form in document and XRD characterization parameter, crystal form and Yuan Yan manufactured in the present embodiment company is special
The crystal form A of sharp CN101573351B report is consistent.The X-ray powder diffraction test chart of this product is shown in Fig. 4.
Claims (10)
1. a kind of preparation and refining methd of amber love song Ge Lieting A crystal form, it is characterised in that with bent Ge Lieting crude free base
It is directly recrystallized in isopropanol and methyl acetate in the mixed solvent, obtains bent Ge Lieting free alkali fine work；With methyl acetate with
Ethyl alcohol is to obtain amber love song Ge Lieting A crystal form at salt using bent Ge Lieting free alkali fine work and one step of succinic acid at salt solvent.
2. a kind of preparation and refining methd of amber love song Ge Lieting A crystal form, it is characterised in that include the following steps:
1) bent Ge Lieting crude product is added to the in the mixed solvent of isopropanol and methyl acetate, is warming up to reflux, after dissolved clarification, slowly
It is cooled to 0-20 DEG C, and continues stirring 5~20 minutes in this temperature；Precipitating, centrifugal rejection filter, filter cake is through isopropanol and methyl acetate
Mixed solvent elution, centrifugal rejection filter to no liquid flow out, obtain bent Ge Lieting fine work；
2) song Ge Lieting fine work is added in methyl acetate, and heating is heated to 30~50 DEG C, and the ethanol solution of succinic acid is slowly dripped
Enter wherein, maintaining reaction temperature is no more than 60 DEG C；It is added dropwise, insulated and stirred 10~60 minutes；Extremely by reaction solution slow cooling
10-40 DEG C, continuing to stir 1-4h, centrifugal filtration in this temperature, filter cake is eluted through the mixed solvent of methyl acetate and dehydrated alcohol,
Centrifugal filtration to no liquid flows out, and obtains finished product.
3. according to the method described in claim 2, it is characterized in that isopropanol and methyl acetate in the mixed solvent are different in step 1)
The weight ratio of propyl alcohol and methyl acetate is 4-5:1.
4. according to the method described in claim 2, it is characterized in that slow cooling is to 5-10 DEG C in step 1)；Mixing time is 8-
12 minutes.
5. according to the method described in claim 2, it is characterized in that in step 2) in the ethanol solution of succinic acid succinic acid weight
Amount percentage is 8-12%.
6. according to the method described in claim 2, it is characterized in that in step 2) methyl acetate and dehydrated alcohol mixed solvent
The weight ratio of middle methyl acetate and dehydrated alcohol is 4-5:1.
7. according to the method described in claim 2, it is characterized in that heating up in step 2) is heated to 40~50 DEG C, preferably 42~48
℃。
8. according to the method described in claim 2, it is characterized in that maintaining reaction temperature is no more than 48 DEG C in step 2).
9. according to the method described in claim 2, it is characterized in that insulated and stirred 20-40 minutes in step 2).
10. according to the method described in claim 2, it is characterized in that by reaction solution slow cooling to 20-30 DEG C in step 2), in
This temperature continues to stir 2-2.5h.
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