CN104230917A - Hydrates of proline derivative salt and production method thereof - Google Patents
Hydrates of proline derivative salt and production method thereof Download PDFInfo
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Abstract
The invention provides hydrates of a proline derivative salt, namely, 2.5-3.5 hydrate crystals of 3-{(2s,4s)-4-4[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidine-2-ylcarbonyl}thiazolidine 2.5 hydrobromide serving as dipeptidyl peptidases (i.e. DPP-IV) inhibitors. The crystals have the advantages of excellent stability and solubility as well as reproducibility and the invention also provides a production method of the crystals.
Description
Technical field
The present invention relates to the new 3-{ (2s of effect two peptidyl enzyme-IV (i.e. DPP-IV) inhibitor, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } salt of thiazolidine and solvate thereof, be specifically related to 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } 2.5 to 3.5 hydrates of thiazolidine 2.5 hydrobromate.
Background technology
DPP-IV identifies that second amino acid is the aminoacid sequence of proline(Pro) (also can be L-Ala or oxyproline) from nitrogen end, produce the Serine (Xaa represents arbitrary amino acid, and Pro represents proline(Pro)) of dipeptides Xaa-Pro.DPP-IV is known to be distributed widely in mammalian tissues, is present in especially in blood, kidney, intestinal tube epithelium and placenta.
DPP-IV inhibitor suppresses the inactivation of glucagon-like-peptide-1 in blood plasma, and strengthens their incretin effect.Therefore, they are useful as the medicine for diabetes etc., and as the potential effective medicine being used for the treatment of diabetes, particularly diabetes B under research and development.
Up to the present, reported a lot of DPP-IV inhibitor, but their blocking-up is active, security in vivo and stability are not ideal, can't meet the demands as pharmaceuticals.So people expect to develop the result for the treatment of with DPP-IV blocking effect and the compound that can meet again as pharmaceuticals.
International Patent Publication No. is that WO02/14271 reports and a series ofly has in the inhibiting tetrahydrothiazole derivates of DDP-IV, wherein, 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } thiazolidine (Compound I), structural formula is as follows, is noticeable.Although this invention is Compound I with the formal description of 3 hydrochlorides, on pharmacology, the stability of this salt and water absorbability are not all very desirable, and reappear the technics comparing difficulty of this salt.Especially, in order to meet the management expectancy in medicament production exploitation, the compound of some quality needs to produce with having reproducibility.Therefore, these character of observing in 3 hydrochlorides of Compound I are considered to be unfavorable for the exploitation of medicament production.
And, although the specific salts of this disclosure of the invention Compound I and tetrahydrothiazole derivates thereof are as embodiment compound, do not find the discussion of the polymorph crystals about embodiment compound.
Chinese Patent Application No. is 200680004865.9,201110303581.2 and 201110303552.6 salt disclosing organic or inorganic unitary, binary or the triprotic acid of a series of Compound I, or its solvate.Wherein, what pay close attention to the most is 2.0 hydrobromates of Compound I or 2.5 hydrobromates of its hydrate and Compound I or its 1.0 to 2.0 hydrate crystal forms.
The present inventor is in research process, find 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } also there is heteromorphism in thiazolidine 2.5 hydrobromate, and found to be different from crystal formation disclosed in above-mentioned patent, this crystal formation is different from the hydrate of 2.0 hydrobromates of Compound I disclosed in above-mentioned Chinese patent in the multiple physical propertiess in hereafter list.As can be seen from the data in table 1, crystal formation of the present invention has excellent characteristic, and solubleness is large, this contribute to medicine better in biology by absorption and distribution and contribute to preparing in a liquid carrier.
Table 1
Summary of the invention
One object of the present invention, discloses 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } crystal of 2.5 to 3.5 hydrates of thiazolidine 2.5 hydrobromate.
Another object of the present invention, disclose 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } preparation method of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate.
The invention provides a kind of 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate, the crystal form X ray powder diffraction charateristic avsorption band (2 θ) of this crystal and D value as follows, error is ± 0.2 °, in table 2.
Table 2
| peak number | diffraction angle (2 θ) | d value | i/I. |
| 1 | 6.001 | 14.715 | 97.0 |
| 2 | 8.057 | 10.965 | 48.4 |
| 3 | 11.725 | 7.542 | 30.9 |
| 4 | 15.370 | 5.76 | 53.8 |
| 5 | 16.603 | 5.335 | 85.7 |
| 6 | 18.484 | 4.796 | 51.8 |
| 7 | 19.865 | 4.466 | 53.1 |
| 8 | 21.221 | 4.183 | 64.5 |
| 9 | 21.678 | 4.096 | 75.9 |
| 10 | 22.235 | 3.995 | 89.6 |
| 11 | 23.324 | 3.811 | 96.3 |
| 12 | 25.154 | 3.538 | 100.0 |
| 13 | 27.387 | 3.254 | 81.4 |
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Crystal of the present invention is a kind of form containing 2.5 to 3.5 crystal water.By following 2 θ: 6.0,16.6,22.2,23.3,25.2 and the feature XRDP peak at degree place, 27.4+/-0.2, and/or IR-peak v
max(KBr) cm
-1: 692,758,914,1106,1176,1257,1383,1457,1559,1653 ~ 1648,2200 ~ 2600,2800 ~ 3000 and 3300 ~ 3500+/-4cm
-1identified.As used in this article, the +/-0.2 degree at XPRD peak and the 4cm at IR peak
-1be suitable for each listed peak respectively.Further, the peak listed by often kind of form is not used in and represents detailed inventory.
The DSC scanning of crystal of the present invention is presented at 83.2 DEG C, has observed crystal water and has lost; At 229.7 DEG C, observe crystal and start fusing.TGA shows evaporating all crystal water lower than 120 DEG C.
The invention also discloses 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } preparation method of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate.By 3-{ (2s under room temperature condition, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } thiazolidine is dissolved in the water of the volume of 2 times of thiazolidine quality, stir, 15 DEG C are maintained the temperature at when product all dissolves, when adularescent solid is separated out, keep this temperature to continue stirring filter after 30 minutes, then forced air drying 5 hours at 40 DEG C, obtain 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } white crystalline powder of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate.
The hydrate of above-mentioned 2.5 to 3.5 hydrobromates, the hydrate of described salt has at 37 DEG C the solubleness being not less than 210mg/mL in water.
The hydrate of above-mentioned 2.5 to 3.5 hydrobromates, the hydrate of described salt is the solubleness in the water of 9 to 13 with 111mg/mL at pH.
Accompanying drawing explanation
[0022] Fig. 1 is 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } X-ray diffractogram of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate.
Fig. 2 is 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } the TGA spectrum of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate.
Fig. 3 is 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } the DSC spectrum of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate.
Embodiment
The present invention will be further described below in conjunction with specific embodiments, but protection content of the present invention is not limited thereto.
The present invention prepares 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } route of thiazolidine 2.5 hydrobromate is as follows:
Embodiment 1: 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] the pyrrolidin-2-yl carbonyl of tertiary butyl oxycarbonyl protection } preparation of thiazolidine (compounds Ⅳ)
Compound II per (110.8g is added in 1000mL single port flask, 0.3mol), compound III (100g, 0.3mol), dissolve with toluene (2500mL), stirring about 1h under room temperature condition to solution is clear state, divides and adds sodium triacetoxy borohydride (211.8g three times, 1mol), stopped reaction after HPLC detection reaction completes.Saturated ammonium chloride solution washs, and aqueous layer with ethyl acetate extracts, and merges organic relevant dry, is evaporated to dry, obtains faint yellow solid 200g.
After dissolving the faint yellow solid of above-mentioned gained with methylene dichloride (400mL), add triethylamine (100mL), aceticanhydride (250mL), stir under room temperature condition, stopped reaction after HPLC detection reaction completes.Adjust ph to 8, with saturated ammonium chloride solution washing after the washing of 1mol/L NaOH solution, water layer dichloromethane solution extracts, and drying is concentrated into dry, obtains compound IV (192g, faint yellow solid).
Embodiment 2:3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } preparation of thiazolidine (Compound I)
With methyl alcohol (1800mL) dissolved compound IV to clear state, slowly add concentrated hydrochloric acid solution (1050mL), after reacting 2h at 30 DEG C, detection reaction is complete.Concentration of reaction solution is to dry, and ethyl acetate washs 3 times, organic layer 0.5mol/L salt acid elution 1 time, combining water layer, cooling, adjust ph to 12, extraction into ethyl acetate, concentrate drying obtains crude product (257g, light gray solid), crude product, through column chromatography, obtains Compound I (101g, 91%, faint yellow solid).
Embodiment 3:3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } preparation of thiazolidine 2.5 hydrobromate (compound V)
With Virahol (1480mL) dissolved compound I (185g, 0.43mol), be heated to reflux state, add 40%HBr solution (116mL), cool after backflow 2h, filter, washed with isopropyl alcohol filter cake, obtain solid chemical compound V (360g, reddish Solid).
Embodiment 4:3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } thiazolidine 2.5 hydrobromate (compound V) refining
Ethanol (2400mL) and above-mentioned gained solid is added in the there-necked flask of 3000mL, pure water (24mL) is added after being heated to reflux state, slowly cool to 40C, suction filtration, obtain solid (311g), oven dry obtains compound V (222g, 81%), purity 99.79%.
Embodiment 5:3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } the re-refining of thiazolidine 2.5 hydrobromate (compound V)
In solid obtained above, add ethanol (1600mL), pure water (16mL), be heated to 80 DEG C of slow coolings to 40 DEG C after solid dissolves completely, filter, dry filter cake and obtain solid (185g).
Embodiment 6:3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } preparation of 2.5 to 3.5 hydrate crystals of thiazolidine 2.5 hydrobromate
Get solid obtained above (5.0g), be dissolved in the water (10mL) and stir, maintaining the temperature at 15 DEG C until completely dissolved, filtering continue to keep this temperature to stir 30min when slow adularescent crystal is separated out after, 40 DEG C of forced air drying 5h, must this crystal.
EXPERIMENTAL EXAMPLE 1
The measurement of solubleness
(1) measurement of solubleness in water
As measuring method, use visual observation, it can conveniently by a small amount of sample evaluation solubleness roughly.Temperature during measurement controls at 37 DEG C.Being placed on by crystal of the present invention (105mg) has in the sample bottle of nut, adds testing liquid (0.5mL) and is screwed thereon by lid.By sample ultrasonic 1min to produce dispersion, to put it in the oscillation mode water bath with thermostatic control being stabilized in 37 DEG C and the 1h that vibrates, then confirm to dissolve by visual observation.The solubleness that result shows crystal of the present invention is not less than 210mg/mL.
(2) measure in the solubleness of pH9-13
Utilizing NaOH, 0.1mol/LNaCl mixing solutions of 0.2mol/L as testing liquid, is the solubleness of the crystal of the invention of 9-13 by pH under liquid-phase chromatographic analysis room temperature.As a result, described solubleness is 66.1mg/mL-152.2mg/mL.From above-mentioned, infer that the solubleness of crystal of the present invention is 111mg/mL.
Table 3
Industrial usability
Crystal formation of the present invention has excellent characteristic, and solubleness is large, this contribute to medicine better in biology by absorption and distribution and contribute to preparing in a liquid carrier, and then promote that Compound I is as the exploitation of medicament production.
Claims (5)
1.3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } crystal of 2.5 to 3.5 hydrates of thiazolidine 2.5 hydrobromate.
2. crystal according to claim 1, it is characterized in that this crystal have comprise following 2 θ: 6.0,16.6,22.2,23.3,25.2 and degree place, 27.4+/-0.2 peak XRDP figure.
3. crystal according to claim 1 and 2, is characterized in that this crystal has and comprises following peak: 692,758,914,1106,1176,1257,1383,1457,1559,1653 ~ 1648,2200 ~ 2600,2800 ~ 3000 and 3300 ~ 3500+/-4cm
-1iR spectrum.
4. produce the method for crystal as claimed in claim 1, described method comprises the step with water recrystallization.
5. method according to claim 4, it is characterized in that comprising the following steps: under room temperature condition by 3-{ (2s, 4s)-4-4 [4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl } thiazolidine is dissolved in the water of the volume of 2 times of thiazolidine 2.5 hydrobromate quality, stir, 15 DEG C are maintained the temperature at when product all dissolves, when adularescent solid is separated out, keep this temperature to continue stirring filter after 30 minutes, then forced air drying 5 hours at 40 DEG C, obtains the crystal described in power 1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105085510A (en) * | 2015-09-11 | 2015-11-25 | 沧州那瑞化学科技有限公司 | Preparation method of (S)-4-oxo-2-(thiazolidine-3-carbonyl) pyrrolidone-1-carboxylic acid tert-butyl ester |
| CN108341818A (en) * | 2017-01-21 | 2018-07-31 | 南京华威医药科技开发有限公司 | Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof |
| CN108727364A (en) * | 2017-04-18 | 2018-11-02 | 乳源东阳光药业有限公司 | A kind of hydrobromic acid is unformed and preparation method thereof for Ge Lieting |
| WO2019205021A1 (en) * | 2018-04-25 | 2019-10-31 | 乳源东阳光药业有限公司 | Amorphous teneligliptin hydrobromide and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085510A (en) * | 2015-09-11 | 2015-11-25 | 沧州那瑞化学科技有限公司 | Preparation method of (S)-4-oxo-2-(thiazolidine-3-carbonyl) pyrrolidone-1-carboxylic acid tert-butyl ester |
| CN105085510B (en) * | 2015-09-11 | 2018-03-02 | 沧州那瑞化学科技有限公司 | A kind of preparation method of the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1 |
| CN108341818A (en) * | 2017-01-21 | 2018-07-31 | 南京华威医药科技开发有限公司 | Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof |
| CN108727364A (en) * | 2017-04-18 | 2018-11-02 | 乳源东阳光药业有限公司 | A kind of hydrobromic acid is unformed and preparation method thereof for Ge Lieting |
| WO2019205021A1 (en) * | 2018-04-25 | 2019-10-31 | 乳源东阳光药业有限公司 | Amorphous teneligliptin hydrobromide and preparation method thereof |
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