CN110540528A - novel piperazine ferulate crystal form I and preparation method thereof - Google Patents
novel piperazine ferulate crystal form I and preparation method thereof Download PDFInfo
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- OEWLZTGXBCJPKL-MSEGBBJSSA-N (e)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid;piperazine Chemical compound C1CNCCN1.COC1=CC(\C=C\C(O)=O)=CC=C1O.COC1=CC(\C=C\C(O)=O)=CC=C1O OEWLZTGXBCJPKL-MSEGBBJSSA-N 0.000 title claims abstract description 72
- 239000013078 crystal Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 11
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 37
- 229940114124 ferulic acid Drugs 0.000 claims description 37
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 37
- 235000001785 ferulic acid Nutrition 0.000 claims description 37
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 37
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 36
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 22
- 238000010438 heat treatment Methods 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- 229960005141 piperazine Drugs 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 229960003506 piperazine hexahydrate Drugs 0.000 claims description 6
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 229960003641 piperazine hydrate Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- QUZFOXSSCPUPDG-UHFFFAOYSA-N piperazine;propan-2-ol Chemical compound CC(C)O.C1CNCCN1 QUZFOXSSCPUPDG-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- KHCWBCVTCIXCCB-UHFFFAOYSA-N methanol;piperazine Chemical compound OC.C1CNCCN1 KHCWBCVTCIXCCB-UHFFFAOYSA-N 0.000 description 3
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 3
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 3
- 235000012141 vanillin Nutrition 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- IHKNVZISLLDMOR-UHFFFAOYSA-N O-Acetylferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1OC(C)=O IHKNVZISLLDMOR-UHFFFAOYSA-N 0.000 description 2
- IHKNVZISLLDMOR-GQCTYLIASA-N O-acetylferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1OC(C)=O IHKNVZISLLDMOR-GQCTYLIASA-N 0.000 description 2
- 238000003684 Perkin reaction Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- AUJXJFHANFIVKH-GQCTYLIASA-N trans-methylferulate Chemical compound COC(=O)\C=C\C1=CC=C(O)C(OC)=C1 AUJXJFHANFIVKH-GQCTYLIASA-N 0.000 description 2
- 235000015099 wheat brans Nutrition 0.000 description 2
- MUQIDFWDLOFXEP-UHFFFAOYSA-N 3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid;piperazine Chemical compound C1CNCCN1.COC1=CC(C=CC(O)=O)=CC=C1O MUQIDFWDLOFXEP-UHFFFAOYSA-N 0.000 description 1
- 241000213006 Angelica dahurica Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 208000022461 Glomerular disease Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- 241000112528 Ligusticum striatum Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000010353 central nervous system vasculitis Diseases 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 108010041969 feruloyl esterase Proteins 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000852 glomerular disease Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- JTLOUXXZZFFBBW-UHFFFAOYSA-N isoferulic acid methyl ester Natural products COC(=O)C=CC1=CC=C(OC)C(O)=C1 JTLOUXXZZFFBBW-UHFFFAOYSA-N 0.000 description 1
- XDROKJSWHURZGO-UHFFFAOYSA-N isopsoralen Natural products C1=C2OC=CC2=C2OC(=O)C=CC2=C1 XDROKJSWHURZGO-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- AUJXJFHANFIVKH-UHFFFAOYSA-N methyl cis-ferulate Natural products COC(=O)C=CC1=CC=C(O)C(OC)=C1 AUJXJFHANFIVKH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- -1 oligosaccharide ferulic acid ester Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- CMFNMSMUKZHDEY-UHFFFAOYSA-N peroxynitrous acid Chemical compound OON=O CMFNMSMUKZHDEY-UHFFFAOYSA-N 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- MLMVLVJMKDPYBM-UHFFFAOYSA-N pseudoisopsoralene Natural products C1=C2C=COC2=C2OC(=O)C=CC2=C1 MLMVLVJMKDPYBM-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel piperazine ferulate crystal form I, wherein the X-ray powder diffraction pattern of the novel piperazine ferulate crystal form I comprises the following components in a 2 theta value: the positions of 12.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.5 +/-0.2 degrees and 29.1 +/-0.2 degrees have characteristic diffraction peaks. The crystal form has stable physicochemical properties, and is suitable for the manufacture of various preparations.
Description
Technical Field
the invention relates to the field of pharmaceutical chemistry, and in particular relates to a novel piperazine ferulate crystal form I and a preparation method thereof.
Background
ferulic acid is a phenolic acid commonly existing in plants, is particularly rich in Chinese angelica, and is also called angelicin. Ferulic acid is a well-known natural antioxidant, has good scavenging effect on hydrogen peroxide, superoxide radical, hydroxyl radical and peroxynitrite, and can regulate physiological function, inhibit enzyme generating free radical, and increase activity of enzyme eliminating free radical; besides, ferulic acid has other health care functions, such as antibiosis and antiphlogosis, tumor inhibition, hypertension prevention and treatment, female ovary protection, liver injury inhibition and the like. Ferulic acid is easily absorbed by human body, can be metabolized and discharged from urine, has extremely low toxicity and is safer to use, and the medicinal value of ferulic acid is more and more emphasized.
Piperazine ferulate is a chemical synthesized medicine according to the main component of traditional Chinese medicine ligusticum wallichii, and has the functions of anticoagulation, platelet aggregation resistance, capillary vessel dilation, coronary flow increase and vasospasm relief. The product is suitable for adjuvant treatment of glomerular diseases complicated with hematuria under the mirror and hypercoagulability, such as nephritis, chronic nephritis, early uremia of nephrotic syndrome, coronary heart disease, cerebral infarction, and vasculitis. Small side effect, no drug tolerance, lasting curative effect and good market prospect. The chemical name is as follows: piperazine 3-methoxy-4-hydroxycinnamic acid, molecular formula C24H30N2O 8. The structural formula is as follows:
There are three main methods for the preparation of ferulic acid: alkali hydrolysis, enzyme hydrolysis and chemical synthesis.
1. the hydrolysis method of alkaline liquor is a semi-synthesis method for preparing ferulic acid, ferulic acid in plants is usually crosslinked with polysaccharide and lignin to form a part of high molecular polymer through ester bond, the ester bond is broken by an alkaline method or an enzymatic method to release ferulic acid, and then proper solvent is adopted for extraction. The sodium hydroxide solution with low concentration is usually adopted, most of ferulic acid in the wheat drum can be released at a proper extraction temperature, and the recovery rate of the ferulic acid can be increased by adding a sodium sulfite protective agent or continuously charging nitrogen in the extraction process. In the whole process of preparing ferulic acid, the method is mainly characterized by purification, extraction method is usually adopted for extracting crude ferulic acid, chromatographic column separation and purification are required for purification of ferulic acid, the process is complicated, the purification is difficult, and large-scale industrialization is difficult.
2. the enzyme hydrolysis method comprises culturing an enzyme to free ferulic acid from methyl ferulate, oligosaccharide ferulic acid ester and polysaccharide ferulic acid. For example, Aspergillus niger is used as a strain, a liquid submerged fermentation method is adopted to prepare a mixed enzyme preparation containing ferulic acid esterase and araboxyenase, the mixed enzyme preparation is adopted to act on wheat bran subjected to starch removal, and ferulic acid is released after the wheat bran is degraded. The method for preparing ferulic acid by decomposing raw materials with biological enzyme is an ideal method with wide application prospect, but an efficient production method cannot be researched at present, and how to efficiently culture and enrich the special enzyme preparation is still to be further researched.
3. The chemical synthesis method is a main method for producing ferulic acid at present, mainly adopts a chemical synthesis method for preparation, takes vanillin and malonic acid as raw materials, and is synthesized through Knoevenagel or Perkin reaction, the synthesis route is simple, the raw materials are low in price, and high-purity ferulic acid can be obtained.
route one: chinese Journal of pharmaceutical industry of China, China Journal of Pharmaceuticals1997,28(4)
The synthesis route is simple, the catalyst is pyridine, aniline and the like, the solvent and the water-carrying agent are toluene, the raw materials are cheap, the isomers are easy to control, and the high-purity ferulic acid can be obtained.
And a second route: chinese patent CN105566101A (application date 2016.5.11)
Vanillin is used as a raw material, a new ferulic acid synthesis route is provided, the vanillin reacts with acetic anhydride at high temperature in the presence of potassium carbonate through perkin reaction to generate acetyl ferulic acid, and the acetyl ferulic acid is obtained through hydrolysis under alkaline conditions.
piperazine ferulate is an oral solid preparation, and is available in the market in the form of tablets and capsules. Drug polymorphism may affect the stability and dissolution rate and content uniformity of oral solid formulations. Therefore, the development of a drug crystal form with good stability has important significance for the development of the preparation.
disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel piperazine ferulate crystal form I with good stability.
the technical scheme adopted by the invention for solving the technical problems is as follows:
the X-ray powder diffraction pattern of the novel piperazine ferulate crystal form I comprises the following components in terms of 2 theta value: the positions of 19.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.5 +/-0.2 degrees and 29.1 +/-0.2 degrees have characteristic diffraction peaks.
In a preferred embodiment of the novel piperazine ferulate form I provided by the present invention, the X-ray powder diffraction pattern of the novel piperazine ferulate form I further comprises characteristic diffraction peaks at positions with 2 θ values of 6.1 ± 0.2 °, 12.9 ± 0.2 °, 13.9 ± 0.2 °, 17.5 ± 0.2 °, 18.3 ± 0.2 °, 18.9 ± 0.2 °, 26.4 ± 0.2 °, 28.7 ± 0.2 °, and 31.9 ± 0.2 °.
In a preferred embodiment of the novel piperazine ferulate crystal form I provided by the invention, a DSC scan of the novel piperazine ferulate crystal form I has an endothermic peak at 167-172 ℃.
In a preferred embodiment of the novel piperazine ferulate crystal form I provided by the invention, the TGA scan of the novel piperazine ferulate crystal form I is decomposed and weightless when heated to 169-173 ℃.
The preparation method of the novel piperazine ferulate crystal form I comprises the following steps:
The method comprises the following steps: dissolving ferulic acid in an alcohol and/or water solvent, heating to dissolve ferulic acid, wherein the dissolving temperature is 30-100 ℃, and obtaining ferulic acid solution;
Step two: slowly adding alcohol and/or water solution of piperazine into the ferulic acid solution in the step one, stirring to form salt, cooling and crystallizing to separate out piperazine ferulate solid;
specifically, the piperazine ferulate in this embodiment is generally solidified under stirring conditions;
Step three: filtering or centrifugally separating the piperazine ferulate solid separated out in the step two;
Step four: and drying the piperazine ferulate solid obtained by separation under the condition of normal pressure or reduced pressure, wherein the drying temperature is 30-80 ℃, preferably 40-60 ℃, and drying to obtain piperazine ferulate crystal form I.
in a preferred embodiment of the preparation method of the novel piperazine ferulate crystal form I, the alcohol in the first step and the alcohol in the second step are selected from one of methanol and isopropanol, and in this embodiment, isopropanol is preferred.
In a preferred embodiment of the preparation method of the novel piperazine ferulate crystal form I, in the second step, the piperazine includes one of anhydrous piperazine and piperazine hexahydrate.
in a preferred embodiment of the preparation method of the novel piperazine ferulate crystal form I, in the second step, the molar ratio of piperazine to ferulic acid is 1-1.2: 2.
In a preferred embodiment of the preparation method of the novel piperazine ferulate crystal form I, the second step is performed by stirring for a salt forming reaction for 0.5-3 hours, and the cooling crystallization temperature is 0-60 ℃, preferably 10-30 ℃.
Compared with the prior art, the novel piperazine ferulate crystal form I provided by the invention has the beneficial effects that: the novel piperazine ferulate crystal form I prepared by the invention has stable physicochemical properties and is suitable for manufacturing various preparations; the preparation process is simple and convenient, can be completed by adopting common equipment and mild conditions, and is suitable for industrial production.
drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive efforts, wherein:
FIG. 1 is an X-ray diffraction diagram of a novel piperazine ferulate crystal form I provided by the invention;
figure 2 is a TGA diagram of novel piperazine ferulate crystalline form I provided by the present invention;
FIG. 3 is a DSC of novel piperazine ferulate form I provided by the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1, the X-ray powder diffraction pattern of the novel piperazine ferulate form I comprises the following values at 2 θ: the positions of 19.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.5 +/-0.2 degrees and 29.1 +/-0.2 degrees have characteristic diffraction peaks.
Furthermore, the X-ray powder diffraction pattern of the novel piperazine ferulate crystal form I also comprises characteristic diffraction peaks at positions with 2 theta values of 6.1 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.4 +/-0.2 degrees, 28.7 +/-0.2 degrees and 31.9 +/-0.2 degrees.
Specifically, the X-ray powder diffraction pattern of the novel piperazine ferulate crystal form I also comprises a characteristic diffraction peak with a 2 theta value shown in figure 1.
Specifically, the X-ray powder diffraction test of the novel piperazine ferulate crystal form I is completed by CuK alpha source determination of a Japan Shimadzu XRD-6000 type X-ray diffractometer at the ambient temperature and the ambient humidity. In the test process, due to the influence of various factors such as the granularity of a test sample, the processing method of the sample during the test, instruments, test parameters, test operation and the like, the peak-appearing position or the peak intensity of an X-ray powder diffraction pattern measured by the same crystal form has certain difference. The experimental error of the diffraction peak 2 theta value in the X-ray powder diffraction pattern can be +/-0.2 degrees. The "ambient temperature" is generally 0 to 40 ℃; "ambient humidity" is typically 30% to 80% relative humidity.
Referring to fig. 3, a scanning image of DSC of the novel piperazine ferulate form I has an endothermic peak at 167-172 ℃.
referring to fig. 2, the TGA scan of the novel piperazine ferulate crystalline form I is decomposed and lost weight when heated to 169-173 ℃.
Specifically, the DSC-TGA analysis condition of the novel piperazine ferulate crystal form I is completed by a test of a Switzerland Mettler 1100LF type instrument at ambient temperature and ambient humidity. Blowing high-purity Ar gas at the flow rate of 50ml/min, and carrying out temperature programming at the speed of 10 ℃/min, wherein the temperature rise range is from room temperature to 300 ℃ for testing. The "ambient temperature" is generally 0 to 40 ℃; "ambient humidity" is typically 30% to 80% relative humidity.
in order to make the technical problems and the beneficial effects solved by the present invention more clear, the novel piperazine ferulate form I is further described in detail below with reference to different embodiments.
the first embodiment is as follows:
Preparation of anhydrous piperazine isopropanol alcohol solution: weighing 17.74g of anhydrous piperazine, adding the anhydrous piperazine into 88ml of isopropanol, slightly heating to 40 ℃ to prepare a clear and transparent anhydrous piperazine isopropanol solution, and cooling to room temperature after preparation;
adding 80.00g of ferulic acid and 400ml of isopropanol solution into a 1000ml three-neck flask, stirring, heating in an oil bath, heating to 60-65 ℃, slowly dropping anhydrous piperazine isopropanol solution when the solid is completely dissolved to form a clear transparent solution, and reacting at 60-65 ℃ for 3 hours after dropping, wherein a large amount of white solid is separated out in the system;
after the reaction is finished, stopping heating, naturally cooling to room temperature, and performing suction filtration to obtain a piperazine ferulate wet product;
And (3) drying the piperazine ferulate wet product in a 50 ℃ forced air drying oven for 10 hours to constant weight to obtain 96.20g of piperazine ferulate finished product, wherein the molar yield is 98.42%, the purity is 99.902% by HPLC detection, and the maximum single impurity is 0.016%.
example two:
Preparation of piperazine methanol aqueous solution: weighing 44g of piperazine hexahydrate, adding the piperazine hexahydrate into 80ml of 50% methanol aqueous solution, slightly heating to 35 ℃ to prepare clear and transparent piperazine methanol aqueous solution, and cooling to room temperature after preparation;
Adding 80.00g of ferulic acid and 300ml of 50% methanol aqueous solution into a three-neck flask, stirring, heating in an oil bath, heating to 65-70 ℃, slowly dropping piperazine methanol aqueous solution when the solid is completely dissolved to form a clear transparent solution, reacting for 2 hours at 60-65 ℃ after the dropping is finished, and separating out a large amount of white solid in the system;
After the reaction is finished, stopping heating, slowly cooling to 0-5 ℃, and performing suction filtration to obtain a piperazine ferulate wet product;
and (3) drying the piperazine ferulate wet product in a 40 ℃ forced air drying oven for 12 hours until the weight is constant, thus obtaining 88.5g of piperazine ferulate finished product, wherein the molar yield is 90.54%, the purity is 99.62% by HPLC detection, and the maximum single impurity is 0.022%.
Example three:
Preparation of aqueous piperazine solution: weighing 21.3g of anhydrous piperazine, adding the anhydrous piperazine into 60ml of water, slightly heating to 45 ℃ to prepare a clear and transparent piperazine aqueous solution, and cooling to room temperature after preparation;
Adding 80.00g of ferulic acid and 160ml of water into a three-neck flask, stirring, heating in an oil bath, heating to 80-85 ℃, slowly dropping a piperazine water solution when the solid is completely dissolved to form a clear transparent solution, reacting at 80 ℃ for 0.5h after the dropping is finished, stopping heating, slowly cooling to 10-15 ℃, and performing suction filtration to obtain a piperazine ferulate wet product;
And (3) drying the piperazine ferulate wet product in a 50 ℃ forced air drying oven for 12 hours until the weight is constant, thus obtaining 80.5g of piperazine ferulate finished product, the molar yield is 82.3%, the purity is 99.48% by HPLC detection, and the maximum single impurity content is 0.07%.
Example four:
Preparation of piperazine isopropanol aqueous solution: weighing 40g of piperazine hexahydrate, adding the piperazine hexahydrate into 100ml of isopropanol, slightly heating to 40 ℃ to prepare a clear and transparent piperazine isopropanol alcohol aqueous solution, and cooling to room temperature after the preparation is finished;
Adding 80.00g of ferulic acid and 400ml of isopropanol into a three-neck flask, stirring, heating in an oil bath, heating to 75-80 ℃, and slowly dropping piperazine isopropanol aqueous solution when the solid is completely dissolved to form a clear transparent solution. After the dropwise addition is finished, reacting at 80 ℃ for 1h, stopping heating, slowly cooling to 20-30 ℃, and performing suction filtration to obtain a piperazine ferulate wet product;
And (3) drying the piperazine ferulate wet product in a 60 ℃ reduced pressure drying oven for 8 hours until the weight is constant, thus obtaining 91.1g of piperazine ferulate finished product, the molar yield is 93.1%, the purity is 99.48% by HPLC detection, and the maximum single impurity content is 0.07%.
To illustrate the stability of piperazine ferulate form i of the present invention, piperazine ferulate form i prepared in example one was selected for stability study, and the results are shown in the following table:
stability test results of novel piperazine ferulate form I
As can be seen from the table above, the piperazine ferulate crystal form I has good stability and is beneficial to preparing various preparations thereof.
The preparation process of the piperazine ferulate crystal form I is simple and convenient, can be completed by adopting common equipment and mild conditions, and is suitable for industrial production.
the above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (9)
1. A novel piperazine ferulate crystal form I, which is characterized in that: the X-ray powder diffraction pattern of the novel piperazine ferulate crystal form I comprises the following components in terms of 2 theta value: the positions of 19.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.5 +/-0.2 degrees and 29.1 +/-0.2 degrees have characteristic diffraction peaks.
2. Novel piperazine ferulate form I according to claim 1, characterized in that: the X-ray powder diffraction pattern of the novel piperazine ferulate crystal form I also comprises characteristic diffraction peaks at positions with 2 theta values of 6.1 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.9 +/-0.2 degrees, 26.4 +/-0.2 degrees, 28.7 +/-0.2 degrees and 31.9 +/-0.2 degrees.
3. novel piperazine ferulate form I according to claim 1, characterized in that: a scanning image of DSC of the novel piperazine ferulate crystal form I has an endothermic peak at 167-172 ℃.
4. Novel piperazine ferulate form I according to claim 1, characterized in that: the TGA scanning graph of the novel piperazine ferulate crystal form I is decomposed and weightless when heated to 169-173 ℃.
5. The process for the preparation of novel piperazine ferulate form I according to any of claims 1 to 4, characterized in that: the method comprises the following steps:
The method comprises the following steps: dissolving ferulic acid in an alcohol and/or water solvent, heating to dissolve ferulic acid, wherein the dissolving temperature is 30-100 ℃, and obtaining ferulic acid solution;
step two: slowly adding alcohol and/or water solution of piperazine into the ferulic acid solution in the step one, stirring to form salt, cooling and crystallizing to separate out piperazine ferulate solid;
Step three: filtering or centrifugally separating the piperazine ferulate solid separated out in the step two;
step four: and drying the piperazine ferulate solid obtained by separation under the conditions of normal pressure or reduced pressure, wherein the drying temperature is 30-80 ℃, and drying to obtain the piperazine ferulate crystal form I.
6. the process for the preparation of novel piperazine ferulate form I according to claim 5, characterized in that: the alcohol in the first step and the second step is selected from one of methanol and isopropanol.
7. The process for the preparation of novel piperazine ferulate form I according to claim 5, characterized in that: in the second step, the piperazine comprises one of anhydrous piperazine and piperazine hexahydrate.
8. the process for the preparation of novel piperazine ferulate form I according to claim 5, characterized in that: in the second step, the molar ratio of the piperazine to the ferulic acid is 1-1.2: 2.
9. The process for the preparation of novel piperazine ferulate form I according to claim 5, characterized in that: in the second step, stirring for salifying reaction for 0.5-3 h, and cooling and crystallizing at 0-60 ℃.
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