CN113493435A - Amorphous form of compound A benzoate, preparation method thereof and pharmaceutical composition containing amorphous form - Google Patents
Amorphous form of compound A benzoate, preparation method thereof and pharmaceutical composition containing amorphous form Download PDFInfo
- Publication number
- CN113493435A CN113493435A CN202110346748.7A CN202110346748A CN113493435A CN 113493435 A CN113493435 A CN 113493435A CN 202110346748 A CN202110346748 A CN 202110346748A CN 113493435 A CN113493435 A CN 113493435A
- Authority
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- China
- Prior art keywords
- compound
- benzoate
- amorphous
- amorphous form
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940126062 Compound A Drugs 0.000 title claims abstract description 60
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims abstract description 21
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 238000001228 spectrum Methods 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
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- 238000004455 differential thermal analysis Methods 0.000 claims 2
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- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 12
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- -1 (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-yl) carbamate Chemical compound 0.000 description 3
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- 239000005711 Benzoic acid Substances 0.000 description 3
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
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- IXSWMXRAIPXMRH-OAHLLOKOSA-N 2-[[3-[(3r)-3-aminopiperidin-1-yl]-6-methyl-5-oxo-1,2,4-triazin-4-yl]methyl]-4-fluorobenzonitrile Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)C(C)=NN=C1N1CCC[C@@H](N)C1 IXSWMXRAIPXMRH-OAHLLOKOSA-N 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- IYGSUIRVOLFPLD-UHFFFAOYSA-N 1-amino-3-[(2-bromo-5-fluorophenyl)methyl]thiourea Chemical compound NNC(=S)NCC1=CC(F)=CC=C1Br IYGSUIRVOLFPLD-UHFFFAOYSA-N 0.000 description 1
- CZLWYKAZAVYQIK-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(Br)C(CBr)=C1 CZLWYKAZAVYQIK-UHFFFAOYSA-N 0.000 description 1
- CEIKPTLXEHWGMB-XFULWGLBSA-N 2-[[3-[(3R)-3-aminopiperidin-1-yl]-6-methyl-5-oxo-1,2,4-triazin-4-yl]methyl]-4-fluorobenzonitrile benzoic acid Chemical compound OC(=O)c1ccccc1.Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2C#N)c1=O CEIKPTLXEHWGMB-XFULWGLBSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241001572615 Amorphus Species 0.000 description 1
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- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
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- 235000009518 sodium iodide Nutrition 0.000 description 1
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Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
- C07C63/06—Benzoic acid
- C07C63/08—Salts thereof
-
- 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
Abstract
The invention belongs to the field of preparation of pharmaceutical compounds, and particularly relates to an amorphous form of a benzoate compound A and a preparation method thereof. The invention also relates to a pharmaceutical composition containing the amorphous form.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical compounds, and particularly relates to an amorphous form of a compound A benzoate, a preparation method thereof, and a pharmaceutical composition containing the amorphous form.
Background
Dipeptidyl peptidase IV (DPP-IV) is a serine protease that specifically hydrolyzes Xaa-Pro or Xaa-Ala dipeptides at the N-terminus of a polypeptide or protein. DPP-IV is a non-canonical serine protease, and the Ser-Asp-His catalytic triad in the C-terminal region is in reverse order unlike a canonical serine protease.
DPP-IV has a variety of physiologically relevant substrates, such as inflammatory chemokines, normal T-cell expressed and secreted factors (RANTES), eotaxin and macrophage derived chemokines, neuropeptides such as neuropeptide Y (NPY) and substance P5, vasoactive peptides, incretins such as glucagon-like peptide (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP).
Inhibition of DPP-IV in vivo can increase endogenous GLP-1(7-36) levels and reduce the production of its antagonist GLP-1 (9-36). Therefore, DPP-IV inhibitors may be effective in diseases associated with DPP-IV activity, such as type 2 diabetes, diabetic dyslipidemia, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
The DPP-IV inhibitors Sitagliptin (Sitagliptin), Saxagliptin (Saxagliptin), Linagliptin (Linagliptin) and Alogliptin (Alogliptin) show good treatment effects on type 2 diabetes clinically, and are approved to be marketed in the United states. Therefore, DPP-IV inhibitors are currently considered as new therapeutic approaches for the treatment of type 2 diabetes.
International patent application WO2011079778 describes a series of DPP-IV inhibitors of entirely new parent-nuclear structures. The compound A is a compound A, and the chemical name of the compound A is as follows: (R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1, 2, 4-triazin-4 (5H) -yl) methyl) -4-fluorobenzonitrile, formula: c17H19FN6O, molecular weight: 342, the chemical structural formula is shown as the following formula (I):
international patent application WO2015110078a1 discloses a benzoate salt of compound a, WO201511007a1 discloses a crystalline form of compound a benzoate salt and a process for its preparation, WO2017008684a1 discloses a crystalline form of compound a and a process for its preparation, and CN106349215A discloses an amorphous form of compound a benzoate salt and a process for its preparation. The inventors repeated the preparation method disclosed in WO2011079778 to obtain compound a as a yellow oil.
Due to different crystal forms of the solid chemical drugs, various physicochemical properties of the drugs can be changed, the quality of the drugs can be changed, and the effect difference of the drugs in the clinical disease treatment can be caused. For example, crystalline solids have a highly ordered network-like structure, they typically require a large amount of energy to dissolve, and the energy required for a solid chemical drug molecule to escape from the crystal is greater than the energy required to escape from the amorphous or amorphous form. As another example, amorphous forms of many drugs are known to exhibit different dissolution profiles and, in some cases, different bioavailability patterns compared to crystalline forms. For some therapeutic indications, one bioavailability pattern may be favored over another. Therefore, it is desirable to have highly pure amorphous forms of drugs to meet the needs of clinical medication, and also to have highly reproducible processes for their preparation.
In view of the above, it would therefore be desirable if a stable amorphous form of compound a benzoate could be effectively used in a pharmaceutical composition for treating a patient in a disease state by inhibiting DPP-IV.
Disclosure of Invention
The present invention provides a novel amorphous compound a benzoate that has enhanced stability and bioavailability relative to the amorphous state of the compound a benzoate previously disclosed, and is a free flowing powder, providing more options for optimizing the formulation of compound a benzoate formulations.
The chemical name of compound a benzoate is: (R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1, 2, 4-triazin-4 (5H) -yl) methyl) -4-fluorobenzonitrile benzoate, formula: c17H19FN6O·C7H6O2Molecular weight: 464.49, the chemical structural formula is the following formula (II),
the amorphous solid of compound a benzoate has no distinct and sharp diffraction peaks in the X-ray powder diffraction (PXRD) spectrum. It is known in the art that amorphous drug (amorphus) refers to a substance molecule arranged in a completely disordered manner and belonging to a thermodynamically metastable state, so that the PXRD pattern of the amorphous drug is usually represented by no diffraction peak or non-sharp diffraction peaks, and the solid drug with the X-ray powder diffraction (PXRD) pattern showing no sharp characteristic diffraction peak can be called amorphous.
Specifically, the amorphous PXRD spectrogram of the benzoate A does not show obvious and sharp diffraction peaks, and accords with amorphous characteristics. More specifically, the compound a benzoate amorphous PXRD spectrum of the present invention shows non-sharp diffraction peaks, and for the compound a benzoate amorphous shown in fig. 1, the compound a benzoate amorphous PXRD spectrum has a broad and weak non-sharp diffraction peak, namely a broad and weak diffraction peak with 2 θ between 15 ° and 25 °; with respect to fig. 2, the X-ray powder diffraction (PXRD) pattern has a broad and weak non-sharp diffraction peak, a broad and weak diffraction peak with 2 θ between 15 ° and 25 °. Both FIGS. 1 and 2 illustrate that the benzoate salt of Compound A provided by the present invention is present in an amorphous form.
The compound a benzoate amorphous Differential Scanning Calorimetry (DSC) spectrum has no distinct endothermic peak, as shown in fig. 3, and specifically, the spectrum shows: the amorphous Tg temperature was 80.48 ℃. The compound A benzoate in amorphous form also has a DSC spectrum shown in figure 4, and the Tg temperature is 77.28 ℃. The amorphous form of the benzoate salt of compound a has a TG profile as shown in figure 5.
The amorphous form of the benzoate of the compound A has high stability, and the content of the benzoate of the compound A is basically unchanged after the benzoate of the compound A is stored for 6 months under accelerated conditions. Moreover, the amorphous form of the benzoate of compound a has better fluidity than the crystalline form α thereof and the amorphous form disclosed in patent CN201610533117.5, the fluidity relates to the difficulty of processing to form a pharmaceutical dosage, and when the particles of the powdery compound do not easily flow past each other, the formulation professional must consider this fact when developing a tablet or capsule formulation, and needs to add auxiliary materials such as glidant to improve the fluidity, so the amorphous form of the benzoate of compound a of the present invention is more favorable for the formulation of pharmaceutical compositions and pharmaceutical preparations. Moreover, the amorphous form of the benzoate of the compound A has smaller particle size compared with the crystal form alpha and the amorphous form disclosed in patent CN201610533117.5, and is more beneficial to the dissolution of the medicine, thereby being more beneficial to the absorption of the medicine.
The invention also aims to provide a preparation method of the compound A benzoate in an amorphous form, which has a simple process and can be realized under the condition of normal temperature.
And (3) placing the compound A benzoate in a ball mill, adding a proper amount of organic solvent for wet grinding, and preparing the amorphous compound A benzoate. Or directly carrying out dry grinding on the benzoate of the compound A to prepare the amorphous form of the benzoate of the compound A.
The organic solvent is one or a mixture of two of dichloromethane, acetonitrile, methyl tert-butyl ether, benzyl alcohol, dimethyl sulfoxide, isopropanol and tetrahydrofuran.
The compound A can be prepared according to a method disclosed in WO2011079778, and the specific synthetic route and the main reaction conditions are as follows:
the preparation method of the compound A benzoate is as follows: refining the compound A, respectively dissolving benzoic acid and the refined compound A by taking an organic solvent or a mixed solution of the organic solvent and water as a solvent, keeping the internal temperature at 10-35 ℃, dropwise adding an equimolar benzoic acid solution into the compound A solution, washing and filtering the obtained reaction solution, concentrating and drying to obtain the compound A benzoate. The organic solvent is ethanol, tetrahydrofuran or a mixture of two of the ethanol and the tetrahydrofuran in any proportion.
Still another object of the present invention is to provide a pharmaceutical composition containing the above compound a, amorphous benzoate, and one or more pharmaceutically acceptable carriers.
The carrier comprises various pharmaceutic adjuvants, packaging materials, delivery tools and the like, and is selected according to the requirements of the preparation, for example, the adjuvants comprise but are not limited to a disintegrant, a binder, a lubricant and the like, and can be suitable for oral administration, inhalation, parenteral administration or surface use; the dosage form includes, but is not limited to, injection, solution preparation, tablet, capsule, granule, etc., preferably, the pharmaceutical composition can be prepared into tablet.
The pharmaceutical composition can be used for preparing medicines for treating related diseases caused by DPP-IV, in particular type II diabetes.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. compared with the amorphous form disclosed in the prior art, the amorphous form of the compound A benzoate disclosed by the invention has better stability, and provides more choices for optimizing the prescription of the compound A benzoate preparation.
2. Compared with the crystal form alpha of the compound A and the amorphous form disclosed in patent CN201610533117.5, the amorphous form of the compound A benzoate has better fluidity, and is easier to prepare and use a pharmaceutical composition and a pharmaceutical preparation.
3. Compared with the crystal form alpha of the compound A and the amorphous form disclosed by the patent CN201610533117.5, the amorphous form of the compound A benzoate has smaller particle size, and is more beneficial to the dissolution of the medicine, thereby being more beneficial to the absorption of the medicine.
4. The amorphous method for preparing the compound A benzoate is simple and rapid, can be prepared at normal temperature, and is easy for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of amorphous example 3 of Compound A benzoate salt of the present invention
FIG. 2 is an X-ray powder diffraction pattern of amorphous example 4 of Compound A benzoate salt of the present invention
FIG. 3 is a DSC chart of amorphous example 3 of benzoate salt of Compound A of the present invention
FIG. 4 is a DSC chart of amorphous example 4 of Compound A benzoate salt of the present invention
FIG. 5 is a TG spectrum of amorphous example 3 of Compound A benzoate of the present invention
Detailed Description
All the detection data/spectra of the present invention can be obtained by using analytical detection instruments of conventional types in the art and conventional detection methods under detection conditions known in the art, and the present invention will be further described in detail with reference to the following examples and drawings, but the embodiments of the present invention are not limited thereto.
The X-ray powder diffraction (PXRD) spectrogram disclosed by the invention is obtained by detecting with a Pasnake sharp shadow (Empyrean) X-ray powder diffractometer under the detection conditions: Cu-Ka radiation, wavelength
Divergence slit 1/8 degrees, X-ray tube voltage 45kV, X-ray tube current 40mA, scanning range 2-40 degrees (2 theta), step size 0.0262606 degrees, and scanning speed 0.169423 degrees/s.
The DSC spectrogram of the invention is obtained by adopting a scanning calorimeter Q2000 (American TA instrument) for detection, and the detection conditions are as follows: the temperature rise rate is 10 ℃/min, and the temperature is raised from room temperature to a specific temperature.
The TG spectrogram is obtained by adopting a thermogravimetric analyzer Q500 (American TA instrument) for detection, and the detection conditions are as follows: the temperature is increased at a rate of 10 ℃/min and heated from room temperature to a specific temperature.
The ball mill of the invention: a Retsch MM400 ball mill (Leichi, Germany) was used for the milling experiments, with 2 milling platforms and 20mL milling pots, each with two steel balls of 9MM diameter. The frequency set for each grind was 25 Hz.
EXAMPLE 1 preparation of Compound A
Compound a was prepared according to the methods of WO2011079778 specification examples 2 and 3, using the following technical synthetic route:
the compound A is obtained by the reaction of the compound A,1H-NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H), 7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d, 1H),1.47(m,1H),1.12(m,1H).MS:m/z,343(100％,M+1)。
the preparation method comprises the following specific steps:
step A.1-bromo-4-fluoro-2- (isothiocyanatomethyl) benzene (2)
To a solution of 1-bromo-2- (bromomethyl) -4-fluorobenzene (1,5.36g,20.0mmol) in DMF (20mL) was added sodium iodide (1.20g,8.00mmol) and potassium thiocyanate (3.88g,40.0 mmol). The mixture was heated to 80 ℃ under nitrogen atmosphere for reaction for 12 hours, cooled to room temperature, added with 100mL of water and extracted with ethyl acetate (50 mL. times.2), the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give 1-bromo-4-fluoro-2- (isothiocyanatomethyl) benzene (2).
Step B.N- (2-bromo-5-fluorobenzyl) hydrazinothiocarboxamide (3)
A solution of hydrazine hydrate (80%, 2.22g,35.5mmol) in 1, 4-dioxane (20mL) was cooled to 0 deg.C and a solution of 1-bromo-4-fluoro-2- (isothiocyanatomethyl) benzene (2,3.16g,12.8mmol) in 1, 4-dioxane (5mL) was added. The mixture was stirred at room temperature for 2h, 100mL of ice water was added thereto, a solid precipitated, filtered, washed with water, and dried over night with phosphorus pentoxide to give N- (2-bromo-5-fluorobenzyl) hydrazinothiocarbamide (3). MS: M/z, 278 (100%, M +1),280 (100%), 300 (10%, M +23),302 (10%).
Step C. methyl 2- (2- (2-bromo-5-fluorobenzothiocarboxamide) hydrazino) propionate (4)
To a solution of pyruvic acid (352mg,4.00mmol) in methanol (15mL) was added N- (2-bromo-5-fluorobenzyl) hydrazinocarbothioamide (3,1.112g,4.00mmol) followed by 5 drops of concentrated sulfuric acid, the mixture was heated to reflux for 7h, most of the solvent was evaporated, the residue was extracted with ethyl acetate (150mL), the organic layer was washed with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous magnesium sulfate, and concentrated by suction filtration to give methyl 2- (2- ((2-bromo-5-fluorobenzylamino carbothioamide) hydrazino) propionate (4), MS: M/z,362 (100%, M +1), 364 (100%), 384 (60%, M +23),386 (60%).
Step D.4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3-thioxo-3, 4-dihydro-1, 2, 4-triazin-5 (2H) -one
(5)
Dissolving sodium methoxide (0.4M) freshly prepared from sodium (273mg,11.88mmol) and dry methanol (30mL) in 30mL of methanol, adding methyl 2- (2- (2-bromo-5-fluorobenzenethioformamide) hydrazino) propionate (4, 1.434g,3.96mmol), heating and refluxing the mixture for 22h, evaporating most of the solvent, diluting the residue with 100mL of water, adjusting the pH to 1-2 with 2N concentrated hydrochloric acid, extracting with ethyl acetate (50 mL. times.2), washing the combined extraction layers with saturated saline, drying with anhydrous sodium sulfate, vacuum-filtering and concentrating to obtain a crude product, purifying by silica gel column chromatography (eluent: ethyl acetate/petroleum ether ═ 20% -30%), to obtain 4- (2-bromo-5-fluorobenzyl) -6-methyl-3-thio-3, 4-dihydro-1, 2, 4-triazin-5 (2H) -one (5), MS: M/z,330 (65%, M +1),332 (60%, M + 23).
Step E.4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3- (methylthio) -1,2, 4-triazin-5 (4H) -one (6)
4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3-thioxo-3, 4-dihydro-1, 2, 4-triazin-5 (2H) -one (5, 914mg,2.77mmol) was suspended in 15mL of ethanol, followed by the addition of sodium hydroxide (111mg,2.77mmol) followed by iodomethane (787mg,5.54 mmol). The mixture was stirred at room temperature for 10 minutes to give a clear yellow solution, the reaction was diluted with 100mL of water, extracted with ethyl acetate (30mL × 2), the combined extract layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction and concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether: 20 to 25%) to give 4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3- (methylthio) -1,2, 4-triazin-5 (4H) -one (6).1H NMR(400MHz,DMSO,ppm):δ7.73(m,1H),7.16(br,1H),7.05(d,1H),5.09(s,2H), 2.56(s,3H),2.32(s,3H).MS:m/z,344(100％,M+1),346(100％)。
Step F. (R) -tert-butyl (1- (4- (2-bromo-5-fluorophenylmethyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2,4-
Triazin-3-yl) piperidin-3-yl) carbamates (8)
Grinding 4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3- (methylthio) -1,2, 4-triazin-5 (4H) -one (6,180mg, 0.523mmol) and (R) -tert-butylpiperidin-3-ylcarbamate (7,208mg,1.04mmol) for 5 minutes, heating to 135 ℃ under nitrogen atmosphere for reaction for 13 hours, purifying the reaction mixture by silica gel column chromatography (eluent: ethyl acetate/petroleum ether ═ 10 to 50%) to obtain (R) -tert-butyl (1- (4- (2-bromo-5-fluorophenylmethyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-yl) carbamate (8). MS: m/z,496 (100%, M +1), 498 (100%).
Step G. (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2,4-
Triazin-3-yl) piperidin-3-yl) carbamates (9)
To a mixture of sodium carbonate (53mg,0.50mmol), palladium acetate (3mg,0.013mmol) and N-methylpyrrolidone 0.5mL was added 3 drops of isopropanol and 2 drops of water, the mixture was stirred at room temperature for 5 minutes, a solution of (R) -tert-butyl (1- (4- (2-bromo-5-fluorophenylmethyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-yl) carbamate (8,246mg,0.496mmol) in NMP (1.0mL) was added and heated to 140 deg.C, and K was added4[Fe(CN)6].3H2O (190mg,0.496mmol), heating at 140 ℃ for 12h, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate (20mL × 2), combining the organic layers, washing with saturated brine, drying over anhydrous magnesium sulfate, concentrating by suction filtration to give a crude product, and purifying by silica gel column chromatography (eluent: ethyl acetate/petroleum ether: 20-35%) to give (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-yl) carbamate (9): MS: M/z,418 (20%), 443 (100%, M +1),465 (95%, M + 23).
(R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1, 2, 4-triazin-4 (5H) -yl)
Methyl) -4-fluorobenzonitrile (10, Compound A)
To 1mL of a dichloromethane solution of (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4, 5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-yl) carbamate (9,37mg) was added 0.5mL of trifluoroacetic acid, stirred at room temperature for 1 hour, neutralized with a saturated sodium bicarbonate solution, extracted with dichloromethane (10mL × 3), the combined organic layers were dried over anhydrous sodium sulfate, concentrated by suction filtration to give a crude product, purified by silica gel column chromatography (eluent: dichloromethane/methanol/aqueous ammonia 92:6:2) to give (R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1, 2, 4-triazin-4 (5H) -yl) methyl) -4-fluorobenzonitrile (10).
1H NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H), 5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H), 1.12(m,1H).MS:m/z,343(100％,M+1)。
EXAMPLE 2 preparation of Compound A benzoate
Taking 21.0g to 500ml of the refined product of the compound A, adding methanol (63ml) into a reaction bottle for dissolving, adding methyl tert-butyl ether (189ml), continuing stirring for 1-2 h, and cooling to 5-15 ℃. Adding 7.5g of benzoic acid for 10-15 min, and keeping the system temperature at 5-15 ℃. After the addition, carrying out heat preservation reaction for 8-10 h; cooling to about 0-5 ℃, and reacting for 3-4 h in a heat preservation way; the reaction flask was filtered and washed with methyl tert-butyl ether (150ml), the filtrates combined and the filter cake collected. And drying the filter cake at 25-40 ℃ until the solvent residue and the water content are qualified, and discharging to obtain 23.3g of compound A benzoate.
1HNMR(DMSO-d6,400MHz,ppm):δ7.96-7.88(m,3H),7.45-7.26(m,5H),6.80(brs, 3H),5.21(dd,2H),3.41(d,1H),3.11-3.08(m,2H),2.91-2.79(m,2H),2.23(s,3H),1.95-1.91( m,1H),1.78-1.74(m,1H),1.57-1.42(m,2H).MS:m/z,341(100％,M-1),343(100％,M+1).
EXAMPLE 3 preparation of Compound A amorphous benzoate
Compound a benzoate salt about 150mg, dry milled for over 60 minutes to produce an amorphous form of compound a benzoate salt.
The obtained benzoate of compound A has an amorphous X-ray powder diffraction pattern as shown in FIG. 1, a DSC pattern as shown in FIG. 3, and a TG pattern as shown in FIG. 5.
EXAMPLE 4 preparation of amorphous Compound A benzoate salt
Compound a benzoate, about 150mg, was prepared by adding 2 drops of isopropanol and wet milling for more than 2 minutes to give compound a benzoate in amorphous form.
The obtained benzoate of compound A has an amorphous X-ray powder diffraction pattern as shown in figure 2 and a DSC pattern as shown in figure 4.
To summarize: the X-ray powder diffraction patterns of different amorphous batches of samples do not show obvious and sharp diffraction peaks, but when the amorphous samples of the same substance obtained by adopting the corresponding method are detected by adopting the same instrument and the same detection method, the changes of the X-ray powder diffraction patterns are basically consistent, but the heights of the specific peaks corresponding to specific displacements may slightly differ, and the samples are considered to belong to the same amorphous X-ray powder diffraction pattern.
Example 5 preparation of amorphous form disclosed in patent CN201610533117.5 and crystalline form α disclosed in patent CN201510033908.7
According to the preparation method disclosed in the patent CN201610533117.5, the compound A disclosed in the patent CN201610533117.5 is prepared to be amorphous benzoate.
According to the preparation method disclosed by the patent CN201510033908.7, the compound A disclosed by the patent CN201510033908.7 is prepared to obtain the benzoate crystal form alpha.
Example 6 comparative stability experiment
According to 9001 guidelines on stability tests of crude drugs and pharmaceutical preparations in accordance with the fourth guideline of the "chinese pharmacopoeia" 2015 edition, amorphous form of benzoate of compound a obtained in examples 3 and 4 and amorphous form (for short, amorphous form in example 5) obtained according to the preparation method disclosed in patent CN201610533117.5 were precisely weighed, and the obtained amorphous forms were packed in a double-layered medical polyethylene plastic bag, heat-sealed, and packaged with an aluminum-plastic composite film, and heat-sealed. Placing in an accelerated test box, standing at 40 deg.C and RH75 + -5% for 0 and 6 months, sampling, and measuring, wherein the detection method refers to high performance liquid chromatography of 0512 in the fourth division of general rules of Chinese pharmacopoeia 2015 edition, and the instrument: agilent high performance liquid chromatograph, chromatographic column C185 μm, flow rate: 1mL/min, detection wavelength: 229nm, mobile phase: 0.1% phosphoric acid-acetonitrile: water 3: the results are shown in the following table:
from the above results, it can be seen that: the amorphous relative content of benzoate salt of compound a obtained in examples 3 and 4 has a significantly better stability with respect to the amorphous form disclosed in patent CN 201610533117.5.
Example 7 comparative flowability experiment
Weighing a certain amount of benzoate amorphous compound A obtained in example 3 and example 4, and amorphous form obtained according to a preparation method disclosed in patent CN201610533117.5 (referred to as amorphous form in example 5 for short) and crystal form alpha obtained according to a preparation method disclosed in CN201510033908.7 (referred to as crystal form alpha in example 5 for short), and respectively determining the angle of repose of the powder by using a fixed funnel method; the bulk density of the powder was measured by the cylinder tapping method, and the results are shown in the following table:
from the above data it can be seen that: compared with the amorphous form obtained in the patent CN201610533117.5 and the crystal form alpha obtained in the patent CN201510033908.7, the amorphous form of the compound A benzoate prepared in the invention has smaller angle of repose and larger bulk density, and the compound A benzoate provided in the invention has better flowability, which is reflected in that the angle of repose of a new amorphous sample is smaller than that of the crystal disclosed in the patent document, and the bulk density is larger than that of the crystal disclosed in the patent document.
Example 8 particle size comparison
A certain amount of the benzoate amorphous form of the compound a obtained in example 3 and example 4, the amorphous form obtained according to the preparation method disclosed in patent CN201610533117.5 and the crystal form α obtained according to the preparation method disclosed in patent CN201510033908.7 were weighed, and sieved through an 80-mesh standard sieve, and the particle size was measured by a laser particle sizer, and the results are shown in the following table:
from the above data it can be seen that: compared with the amorphous compound obtained in the patent CN201610533117.5 and the crystal form alpha obtained in the patent CN201510033908.7, the compound A benzoate prepared in the invention has smaller particle size, and the compound A benzoate provided in the invention has better dissolution rate.
EXAMPLE 9 preparation of pharmaceutical composition
Compound A benzoate (amorphous) 6.78g
Dextrin 84.00g
The materials are evenly mixed according to a conventional method, and are respectively filled into common gelatin capsules in 1000 equal parts to obtain 1000 capsules.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. An amorphous form of a benzoate salt of compound A, said benzoate salt of compound A having the chemical formula of formula (II),
the method is characterized in that: the amorphous X-ray powder diffraction spectrum has no sharp diffraction peak.
2. The amorphous form of compound a benzoate salt according to claim 1, characterized in that: the amorphous X-ray powder diffraction spectrum has non-sharp diffraction peaks.
3. The amorphous form of compound a benzoate salt according to any one of claims 1 or 2, characterized in that: the amorphous X-ray powder diffraction spectrum has a wide and weak diffraction peak between 15-25 degrees 2 theta.
4. The amorphous form of compound a benzoate salt according to any one of claims 1 to 3, characterized in that: the amorphous powder X-ray diffraction spectrum is shown in figure 1 or figure 2.
5. The amorphous form of compound a benzoate salt according to any one of claims 1 to 4, characterized in that: the amorphous differential thermal analysis spectrum has no obvious endothermic peak.
6. The amorphous form of compound a benzoate salt according to any one of claims 1 to 4, characterized in that: the differential thermal analysis spectrum of the amorphous form is shown in figure 3 or figure 4.
7. The amorphous form of compound a benzoate according to any one of claims 1 to 6, characterized in that: the amorphous TG pattern is shown in figure 5.
8. A process for the preparation of an amorphous form of compound a benzoate according to any one of claims 1 to 7, characterized in that: and (2) putting the compound A benzoate in a ball mill, adding a proper amount of organic solvent for wet grinding to prepare the amorphous compound A benzoate, or directly grinding the compound A benzoate by a dry method to prepare the amorphous compound A benzoate.
9. The method of claim 8, wherein: the organic solvent is one or a mixture of two of dichloromethane, acetonitrile, methyl tert-butyl ether, benzyl alcohol, dimethyl sulfoxide, isopropanol and tetrahydrofuran.
10. A pharmaceutical composition characterized by: the pharmaceutical composition comprises amorphous form of compound a benzoate salt according to any one of claims 1 to 7, and one or more pharmaceutically acceptable carriers.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104803972A (en) * | 2014-01-24 | 2015-07-29 | 深圳信立泰药业股份有限公司 | Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof |
| CN106349215A (en) * | 2015-07-15 | 2017-01-25 | 深圳信立泰药业股份有限公司 | Amorphism of compound A benzoate, preparation method thereof, and amorphism-containing medicinal composition |
| WO2018219295A1 (en) * | 2017-05-31 | 2018-12-06 | 深圳信立泰药业股份有限公司 | Deuterated 1,2,4-triazine derivatives of dipeptidyl peptidase iv inhibitor |
| CN109692164A (en) * | 2017-10-20 | 2019-04-30 | 深圳信立泰药业股份有限公司 | Compound A or the pharmaceutical composition of its salt and preparation method thereof |
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- 2021-03-31 CN CN202110346748.7A patent/CN113493435B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104803972A (en) * | 2014-01-24 | 2015-07-29 | 深圳信立泰药业股份有限公司 | Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof |
| CN106349215A (en) * | 2015-07-15 | 2017-01-25 | 深圳信立泰药业股份有限公司 | Amorphism of compound A benzoate, preparation method thereof, and amorphism-containing medicinal composition |
| WO2018219295A1 (en) * | 2017-05-31 | 2018-12-06 | 深圳信立泰药业股份有限公司 | Deuterated 1,2,4-triazine derivatives of dipeptidyl peptidase iv inhibitor |
| CN109692164A (en) * | 2017-10-20 | 2019-04-30 | 深圳信立泰药业股份有限公司 | Compound A or the pharmaceutical composition of its salt and preparation method thereof |
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