CN113861131A - Preparation method of cetirizine impurity C - Google Patents
Preparation method of cetirizine impurity C Download PDFInfo
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- CN113861131A CN113861131A CN202111316145.9A CN202111316145A CN113861131A CN 113861131 A CN113861131 A CN 113861131A CN 202111316145 A CN202111316145 A CN 202111316145A CN 113861131 A CN113861131 A CN 113861131A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- AMWZYEYIOPBLEO-UHFFFAOYSA-N 2-[2-[4-[(2-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C(=CC=CC=1)Cl)C1=CC=CC=C1 AMWZYEYIOPBLEO-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000002904 solvent Substances 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000012044 organic layer Substances 0.000 claims abstract description 14
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims abstract description 11
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- 150000001875 compounds Chemical class 0.000 claims description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 238000001035 drying Methods 0.000 claims description 29
- 238000005406 washing Methods 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 239000012267 brine Substances 0.000 claims description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- VMHYWKBKHMYRNF-UHFFFAOYSA-N (2-chlorophenyl)-phenylmethanone Chemical compound ClC1=CC=CC=C1C(=O)C1=CC=CC=C1 VMHYWKBKHMYRNF-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000003599 detergent Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002274 desiccant Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 5
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 abstract description 14
- 229960001803 cetirizine Drugs 0.000 abstract description 13
- 239000000126 substance Substances 0.000 abstract description 12
- HDEXHMUQVQUVCA-UHFFFAOYSA-N 1-[4-[2-(2-chlorophenyl)phenyl]piperazin-1-yl]ethanol Chemical compound CC(N(CC1)CCN1C(C=CC=C1)=C1C(C=CC=C1)=C1Cl)O HDEXHMUQVQUVCA-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000002156 mixing Methods 0.000 abstract description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- YMXAYMSJCVGYEM-UHFFFAOYSA-N 1-Chloro-2-(chlorophenylmethyl)benzene Chemical compound C=1C=CC=C(Cl)C=1C(Cl)C1=CC=CC=C1 YMXAYMSJCVGYEM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- ALKWTKGPKKAZMN-UHFFFAOYSA-N 1-chloro-4-[chloro(phenyl)methyl]benzene Chemical compound C=1C=C(Cl)C=CC=1C(Cl)C1=CC=CC=C1 ALKWTKGPKKAZMN-UHFFFAOYSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- ZLYGTXIQYQLAGA-UHFFFAOYSA-N 1-[4-[2-(4-chlorophenyl)phenyl]piperazin-1-yl]ethanol Chemical compound ClC1=CC=C(C=C1)C1=C(C=CC=C1)N1CCN(CC1)C(C)O ZLYGTXIQYQLAGA-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MUZLUPGCGALIKR-UHFFFAOYSA-N 2-[2-[4-[(2-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid dihydrochloride Chemical compound Cl.Cl.OC(=O)COCCN1CCN(CC1)C(c1ccccc1)c1ccccc1Cl MUZLUPGCGALIKR-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- -1 extractant Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000022719 perennial allergic rhinitis Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
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- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of cetirizine impurity C. The method comprises the steps of directly reacting 1-chloro-2- (chlorophenylmethyl) benzene with hydroxyethyl piperazine to prepare a key intermediate 4- { (2-chlorophenyl) phenyl } -1-hydroxyethyl piperazine, then taking 4- { (2-chlorophenyl) phenyl } -1-hydroxyethyl piperazine and tert-butyl bromoacetate as reaction substrates, taking alkali metal hydroxide as a catalyst, mixing dichloromethane and water as a solvent, reacting at room temperature, standing for layering after the reaction is finished, and purifying an organic layer through silica gel column chromatography to obtain the product. The method has the advantages of cheap and easily available raw materials, low toxicity and little pollution; the reaction steps are few, and the preparation period is short; the product is single, the purity is high, the yield is good, and the total yield can reach more than 70%. The prepared cetirizine impurity C standard substance has great significance for the quality research of cetirizine.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of cetirizine impurity C.
Background
Cetirizine (Cetirizine) is the second generation H1Antihistamines, which are long-acting, selective, potent antiallergic agents for oral administration, are used for seasonal or perennial allergic rhinitis, urticaria and pruritus caused by allergens, and have the following structural formula:
the existing preparation method of cetirizine generally comprises the steps of firstly reacting 1-chloro-4- (chlorophenylmethyl) benzene with piperazine, then reacting with 2-chloroethanol to synthesize a key intermediate 4- { (2-chlorophenyl) phenyl } -1-hydroxyethyl piperazine, then condensing with sodium chloroacetate in an inert organic solvent under the action of a catalyst, and then carrying out a series of post-treatments to obtain cetirizine.
Among the many impurities of cetirizine, cetirizine impurity C (chemical name: 2- [ 2- {4- [ (2-chlorophenyl) (phenyl) methyl ] piperazin-1-yl } ethoxy ] -acetic acid dihydrochloride) is a more important one, and its structural formula is as follows:
the impurity can be used for quantitative and qualitative analysis in the processes of production, transportation and storage of cetirizine, so that the quality standard of the cetirizine is improved, and important basis and guidance are provided for safe administration of the cetirizine. Therefore, the preparation of the cetirizine impurity C standard substance has great significance for the quality research of cetirizine. The impurity has a structure similar to that of cetirizine, and can be improved on the existing preparation process of cetirizine to discuss the synthesis process of cetirizine impurity C.
Chinese patent CN101492430A discloses a preparation method of cetirizine hydrochloride, which takes 4- { (4-chlorphenyl) phenyl } -1-hydroxyethyl piperazine and sodium chloroacetate as reaction substrates, takes alkali metal hydroxide as a catalyst, takes DMF or DMSO as a solvent, and carries out reaction at 5-40 ℃. However, the product of the reaction of the method exists in the form of sodium salt, has large polarity and good water solubility, and is difficult to extract from water; secondly, DMF is preferably used as a solvent in the method, so that the product is difficult to extract from water, and is difficult to wash away the DMF, and the extracted product contains a large amount of DMF, which is not beneficial to purification and separation; in the post-treatment, the method preferably uses a toxic reagent toluene as a washing solvent, so that the danger of experimenters is increased, the post-treatment of waste liquid is difficult, and the environment is polluted.
Disclosure of Invention
The invention aims to provide a preparation method of cetirizine impurity C, which can simplify reaction steps, reduce energy consumption and obtain a high-purity product under mild reaction conditions.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a preparation method of cetirizine impurity C comprises the following steps:
(1) preparation of compound a: adding 2-chlorobenzophenone into a reaction bottle, adding a first solvent, stirring at the temperature of-10-10 ℃ at T1, slowly adding sodium borohydride, slowly heating to room temperature for reaction for 2-4h, adding a small amount of water for quenching reaction, spin-drying the first solvent, extracting, drying, and spin-drying to obtain a compound a;
preferably, the temperature T1 is 0 ℃;
preferably, the first solvent is methanol;
preferably, the extractant for extraction is ethyl acetate;
preferably, the dry desiccant is anhydrous sodium sulfate;
wherein the molar mass ratio of the 2-chlorobenzophenone to the sodium borohydride is 1:0.6-0.7,
preferably, the molar mass ratio of the 2-chlorobenzophenone to the sodium borohydride is 1: 0.6.
(2) Preparation of compound b: adding the compound a into a reaction bottle, adding a solvent II, adding concentrated hydrochloric acid, reacting at 40-50 ℃ for 2-4h, adding water after the reaction is finished, extracting, washing an organic layer, drying, and spin-drying to obtain a compound b;
preferably, the solvent II is 1, 4-dioxane;
preferably, the extractant for extraction is ethyl acetate;
preferably, the organic layer is washed with brine;
preferably, the drying is anhydrous sodium sulfate drying;
wherein the molar mass ratio of the compound a to the concentrated hydrochloric acid is 1:5-6,
preferably, the molar mass ratio of the compound a to the concentrated hydrochloric acid is 1: 5.
(3) Preparation of compound c: adding the compound b into a reaction bottle, dissolving in a solvent III, adding potassium carbonate, adding 1- (2-hydroxyethyl) piperazine, heating to 80-90 ℃, reacting for 8-12h, cooling to room temperature after the reaction is finished, filtering, and evaporating filtrate to obtain a compound c, wherein the compound c is a colorless oily substance;
wherein the molar mass ratio of the compound b, potassium carbonate and 1- (2-hydroxyethyl) piperazine is 1:2-3:1-2,
preferably, the molar mass ratio of the compound b, potassium carbonate and 1- (2-hydroxyethyl) piperazine is 1:2: 1;
wherein the solvent III is acetone or acetonitrile.
(4) Preparation of compound d: adding the compound c into a reaction bottle, dissolving in dichloromethane, adding tetrabutylammonium bromide, 35% sodium hydroxide solution and tert-butyl bromoacetate, reacting at room temperature for 6-10h, standing for layering after the reaction is finished, spin-drying an organic layer, and purifying by silica gel column chromatography, wherein the silica gel column uses dichloromethane: washing with methanol at a ratio of 100:1 to obtain a compound d, wherein the compound d is a colorless oily substance;
wherein the molar mass ratio of the compound c to the tetrabutylammonium chloride to the tert-butyl bromoacetate is 1:0.4-0.5:2-3, and preferably, the molar mass ratio of the compound c to the tetrabutylammonium chloride to the tert-butyl bromoacetate is 1:0.5: 2.
(5) Preparation of cetirizine impurity C: adding a compound d into a reaction bottle, dissolving in dichloromethane, adding a dioxane hydrochloride solution, reacting at room temperature for 3-4h, removing dichloromethane under reduced pressure after the reaction is finished, adding ethyl acetate, stirring for 1-2h, filtering the generated white solid, washing, and drying to obtain a cetirizine impurity C.
Preferably, the washing detergent is ethyl acetate.
The reaction process structural formula of the preparation method provided by the invention is as follows:
the above-mentioned preparation method and the selection of reactants, solvent, extractant, drying agent, detergent, etc. in the preparation step thereof, and the selection of reaction conditions such as temperature, time, etc. are all preferable, are not limited to the above selection, and may be replaced or omitted as appropriate depending on the effect.
Compared with the prior art, the invention has the following advantages:
(1) the reaction conditions are conventional, the reaction is basically carried out at room temperature, the highest reaction temperature does not exceed 100 ℃, and the energy consumption is low;
(2) the raw materials are cheap and easy to obtain, and the toxicity is low and the pollution is small;
(3) the product is single, the purity is high, the yield is good, and the total yield can reach more than 70%;
(4) the reaction steps are reduced, the preparation period can be greatly shortened, and the preparation cost is reduced.
Drawings
FIG. 1 is the formula of cetirizine impurity C;
FIG. 2 is a route for the preparation of cetirizine impurity C;
FIG. 3 is a C NMR spectrum of cetirizine impurity;
FIG. 4 is an HPLC profile of cetirizine impurity C;
FIG. 5 is a Cetirizine impurity C mass spectrum.
Detailed Description
The terms as used herein:
"prepared from … …" is synonymous with "comprising". The terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
When an amount, concentration, or other value or parameter is expressed as a range, preferred range, or as a range of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when the range "1 ~ 5" is disclosed, the ranges described should be construed to include the ranges "1 ~ 4", "1 ~ 3", "1 ~ 2 and 4 ~ 5", "1 ~ 3 and 5", and the like. When a range of values is described herein, unless otherwise stated, the range is intended to include the endpoints thereof and all integers and fractions within the range.
"and/or" is used to indicate that one or both of the illustrated conditions may occur, e.g., a and/or B includes (a and B) and (a or B).
The technical solutions of the present invention will be described in detail with reference to specific examples, but those skilled in the art will understand that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.
Example 1
As shown in fig. 2, a preparation method of cetirizine impurity C comprises the following steps:
(1) preparation of compound a: adding 5g of 2-chlorobenzophenone (23.15mmol) into a dry reaction bottle, adding 30mL of anhydrous methanol, stirring at-10 ℃, slowly adding 525mg of sodium borohydride (13.89mmol), slowly heating to room temperature for reaction for 2 hours, after the reaction is finished, adding a small amount of water to quench the reaction, spinning off the methanol, adding 100mL of water into the residue, washing with 100mL of ethyl acetate for 3 times, washing the ethyl acetate layer after layering with brine, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5g of a colorless oily compound a with the yield of 100%.
(2) Preparation of compound b: adding 5g of the compound a (22.93mmol) into a dry reaction bottle, adding 30mL of 1, 4-dioxane, finally adding 9.6mL of concentrated hydrochloric acid (115mmol), heating to 40 ℃ for reaction for 2 hours, after the reaction is finished, adding 100mL of water, washing with 100mL of ethyl acetate for 3 times, washing an ethyl acetate layer after layering with brine, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5.1g of the compound b as a colorless oily substance with the yield of 94%.
(3) Preparation of compound c: adding 5.1g of compound b (21.61mmol) into a dry reaction flask, adding 50mL of acetone, then adding 6.1g of anhydrous potassium carbonate (44mmol), finally adding 2.8 g of N-hydroxyethyl piperazine (21.61mmol) with stirring, mixing and refluxing at 80 ℃ for 8 hours, after the reaction is completed, cooling to room temperature, filtering, removing the solvent from the filtrate under reduced pressure, adding 150mL of ethyl acetate to the residue, washing with 150mL of water for 3 times, washing the organic layer with brine, drying over anhydrous sodium sulfate, removing the solvent under reduced pressure, purifying the residue by silica gel column chromatography, eluting with dichloromethane: methanol 50: 1 column punch to obtain 6.1g of colorless oil compound c in 85% yield.
In the step, a compound b (chemical name: 1-chloro-2- (chlorophenylmethyl) benzene) directly reacts with hydroxyethyl piperazine to obtain a key intermediate, whereas in the prior art, 1-chloro-4- (chlorophenylmethyl) benzene firstly reacts with piperazine and then reacts with 2-chloroethanol to prepare the key intermediate, so that the reaction step and energy consumption are increased, more time is consumed, and the yield is reduced.
(4) Preparation of compound d: 6.1g of compound c (18.48mmol) are introduced into a dry reaction flask, 50mL of dichloromethane are added, then 50mL of 35% sodium hydroxide solution and 1.44g of tetrabutylammonium chloride (7.4mmol) are added, finally 7.22g of tert-butyl bromoacetate (37mmol) are added with stirring, the mixture is reacted at room temperature for 6 hours, after completion of the reaction, the mixture is left to separate by settling, the organic layer is freed of solvent under reduced pressure, and the residue is purified by silica gel column chromatography, purified with dichloromethane: methanol 100:1 column punch gave 7.2g of the compound d as a colorless oil in 87% yield.
Taking a compound d (chemical name: 4- { (2-chlorphenyl) phenyl } -1-hydroxyethyl piperazine) and tert-butyl bromoacetate as reaction substrates, taking an alkali metal hydroxide as a catalyst, taking a mixed solvent of dichloromethane and water, reacting at room temperature, directly standing for layering after the reaction is finished, and purifying an organic layer by silica gel column chromatography to obtain a product; the product has small polarity, simple extraction, no need of repeated extraction and no need of using toluene with high toxicity as a detergent. The product in the prior art exists in a sodium salt form, has high polarity and good water solubility, and is difficult to extract from water; in addition, DMF is used as a solvent in the prior art, so that the product is difficult to extract from water, DMF is difficult to wash away by water, and the extracted product contains a large amount of DMF, which is not beneficial to purification and separation and needs to be repeatedly extracted by toxic toluene.
(5) Preparation of cetirizine impurity C: adding 7.2g of compound d (16.21mmol) into a dry reaction bottle, adding 50mL of dichloromethane, then adding 20mL of dioxane hydrochloride (4.0moL/L) under stirring, reacting at room temperature for 3 hours, removing most of solvent under reduced pressure after the reaction is finished, adding 100mL of ethyl acetate into residue, continuously stirring for 1 hour to generate white solid, filtering, washing the solid with ethyl acetate, and drying to obtain cetirizine impurity C (the structural formula is shown in figure 1), wherein the yield is 100%.
Cetirizine impurity C was characterized by a spectrum such as the hydrogen nuclear magnetic resonance spectrum (1H NMR (600MHz, CHLOROFORM-d) d ppm 2.53-2.76(m,4H)2.95(d, J ═ 5.45Hz,2H)3.10(br.s.,4H) shown in fig. 3
3.71-3.85(m,2H)3.93-4.06(m,2H)4.90(s,1H)7.13(td, J ═ 7.63,1.45Hz,1H)7.18-7.23(m,1H)7.24-7.27(m,2H)7.28-7.31(m,2H)7.41(d, J ═ 7.45Hz,2H)7.78(dd, J ═ 7.72,1.00Hz,1H)12.49(br.s, 1H)), as shown in the HPLC map of fig. 4; as shown in the mass spectrum of FIG. 5, it can be seen that the product prepared by the method is very pure, and the content of other substances is very low.
Example 2
A preparation method of cetirizine impurity C comprises the following steps:
(1) preparation of compound a: adding 5g of 2-chlorobenzophenone (23.15mmol) into a dry reaction bottle, adding 40mL of anhydrous methanol, stirring at 0 ℃, slowly adding 612mg of sodium borohydride (16.2mmol), slowly heating to room temperature for reaction for 3 hours, after the reaction is finished, adding a small amount of water to quench the reaction, spinning off the methanol, adding 120mL of water into the residue, washing with 120mL of ethyl acetate for 2 times, washing the ethyl acetate layer after delamination with brine, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 4.8g of a colorless oily compound a, wherein the yield is 98%.
(2) Preparation of compound b: adding 4.8g of the compound a (22.02mmol) into a dry reaction bottle, adding 30mL of 1, 4-dioxane, finally adding 10.97mL of concentrated hydrochloric acid (132mmol), heating to 45 ℃, reacting for 3 hours, after the reaction is finished, adding 100mL of water, washing 3 times with 100mL of ethyl acetate, washing an ethyl acetate layer after layering with brine, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5g of a colorless oily compound b with the yield of 95%.
(3) Preparation of compound c: adding 5g of compound b (21.19mmol) into a dry reaction flask, adding 50mL of acetonitrile, then adding 8.83g of anhydrous potassium carbonate (63.57mmol), finally adding 5.5 g of N-hydroxyethyl piperazine (42.38mmol) with stirring, mixing and refluxing at 85 ℃ for 10 hours, after the reaction is completed, cooling to room temperature, filtering, removing the solvent from the filtrate under reduced pressure, adding 150mL of ethyl acetate into the residue, washing with 150mL of water for 3 times, washing the organic layer with brine, drying over anhydrous sodium sulfate, removing the solvent under reduced pressure, purifying the residue by silica gel column chromatography, eluting with dichloromethane: methanol 50: 1 column punch to give 6g of compound c as a colorless oil in 88% yield.
(4) Preparation of compound d: 6g of compound c (18.18mmol) are introduced into a dry reaction vessel, 50mL of dichloromethane are added, then 50mL of 35% sodium hydroxide solution and 1.77g of tetrabutylammonium chloride (9.09mmol) are added, finally 10.63g of tert-butyl bromoacetate (54.54mmol) are added with stirring, the mixture is reacted at room temperature for 8 hours, after completion of the reaction, the mixture is left to separate by settling, the organic layer is freed of solvent under reduced pressure, and the residue is purified by chromatography on a silica gel column with dichloromethane: methanol 100:1 column punch gave 7g of the compound d as a colorless oil in 88% yield.
(5) Preparation of cetirizine impurity C: adding 7g of compound d (15.76mmol) into a dry reaction bottle, adding 50mL of dichloromethane, then adding 20mL of dioxane hydrochloride (4.0moL/L) under stirring, reacting at room temperature for 3.5 hours, removing most of solvent under reduced pressure after the reaction is finished, adding 100mL of ethyl acetate into residue, continuously stirring for 1.5 hours to generate white solid, filtering, washing the solid with ethyl acetate, and drying to obtain cetirizine impurity C with the yield of 100%.
Example 3
A preparation method of cetirizine impurity C comprises the following steps:
(1) preparation of compound a: adding 5g of 2-chlorobenzophenone (23.15mmol) into a dry reaction bottle, adding 50mL of anhydrous methanol, stirring at 10 ℃, slowly adding 567mg of sodium borohydride (15mmol), slowly heating to room temperature for reaction for 4 hours, after the reaction is finished, adding a small amount of water to quench the reaction, spinning off the methanol, adding 120mL of water into the residue, washing with 120mL of ethyl acetate for 3 times, washing the ethyl acetate layer after layering with brine, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 4.9g of a colorless oily compound a, wherein the yield is 99%.
(2) Preparation of compound b: adding 4.9g of compound a (22.47mmol) into a dry reaction bottle, adding 30mL of 1, 4-dioxane, finally adding 10.29mL of concentrated hydrochloric acid (123.58mmol), heating to 50 ℃ for reaction for 4 hours, after the reaction is finished, adding 100mL of water, washing 3 times with 100mL of ethyl acetate, washing an ethyl acetate layer after layering with brine, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 5g of compound b as a colorless oily substance with the yield of 95%.
(3) Preparation of compound c: adding 5g of compound b (21.18mmol) into a dry reaction flask, adding 50mL of acetone, then adding 7.35g of anhydrous potassium carbonate (52.95mmol), finally adding 4.13 g of N-hydroxyethyl piperazine (31.77mmol) with stirring, mixing and refluxing at 90 ℃ for 12 hours, after the reaction is completed, cooling to room temperature, filtering, removing the solvent under reduced pressure from the filtrate, adding 150mL of ethyl acetate into the residue, washing 1 time with 150mL of water, washing the organic layer with brine, drying over anhydrous sodium sulfate, removing the solvent under reduced pressure, purifying the residue by silica gel column chromatography, eluting with dichloromethane: methanol 50: 1 column punch gave 6.1g of compound c as a colorless oil in 87% yield.
(4) Preparation of compound d: 6.1g of compound c (18.48mmol) are introduced into a dry reaction flask, 50mL of dichloromethane are added, then 50mL of 35% sodium hydroxide solution and 1.62g of tetrabutylammonium chloride (8.32mmol) are added, finally 9g of tert-butyl bromoacetate (46.2mmol) are added with stirring, the mixture is reacted at room temperature for 10 hours, after completion of the reaction, the mixture is left to separate by settling, the organic layer is freed of solvent under reduced pressure, and the residue is purified by silica gel column chromatography, purified with dichloromethane: methanol 100:1 column punch gave 7g of the colorless oil compound d in 84% yield.
(5) Preparation of cetirizine impurity C: adding 7g of compound d (15.76mmol) into a dry reaction bottle, adding 50mL of dichloromethane, then adding 20mL of dioxane hydrochloride (4.0moL/L) under stirring, reacting at room temperature for 4 hours, removing most of solvent under reduced pressure after the reaction is finished, adding 100mL of ethyl acetate into residue, continuously stirring for 2 hours to generate white solid, filtering, washing the solid with ethyl acetate, and drying to obtain cetirizine impurity C with the yield of 100%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Furthermore, those skilled in the art will appreciate that while some embodiments herein include some features included in other embodiments, rather than other features, combinations of features of different embodiments are meant to be within the scope of the invention and form different embodiments. For example, in the claims above, any of the claimed embodiments may be used in any combination. The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Claims (10)
1. A preparation method of cetirizine impurity C is characterized by comprising the following steps:
(1) preparation of compound a: dissolving 2-chlorobenzophenone in a first solvent, stirring and adding sodium borohydride at a temperature of T1, heating, reacting for T1 time, extracting, drying and spin-drying to obtain a compound a;
(2) preparation of compound b: dissolving the compound a in a second solvent, adding concentrated hydrochloric acid, reacting at the temperature of T2 for T2 time, adding water after the reaction is finished, extracting, washing an organic layer, drying, and spin-drying to obtain a compound b;
(3) preparation of compound c: dissolving the compound b in a solvent III, adding potassium carbonate, adding 1- (2-hydroxyethyl) piperazine, reacting at the temperature of T3 for T3 time, cooling and filtering after the reaction is finished, and evaporating filtrate to dryness to obtain a compound c;
(4) preparation of compound d: dissolving the compound c in dichloromethane, adding tetrabutylammonium bromide, 35% sodium hydroxide solution and tert-butyl bromoacetate, reacting at the temperature of T4 for T4 time, standing for layering after the reaction is finished, spin-drying an organic layer, and purifying by silica gel column chromatography to obtain a compound d;
(5) preparation of cetirizine impurity C: dissolving the compound d in dichloromethane, adding dioxane hydrochloride solution, reacting at T5 for T5 time, removing dichloromethane under reduced pressure after the reaction is finished, adding ethyl acetate, stirring for a period of time, filtering, washing and drying to obtain cetirizine impurity C.
2. The method for preparing cetirizine impurity C according to claim 1, wherein the compound a has a structural formula
The structural formula of the compound b is
The structural formula of the compound c is
The structural formula of the compound d is
3. The process for the preparation of cetirizine impurity C according to claim 1, characterized in that said step (1) satisfies one or more of the following conditions:
A. the molar mass ratio of the 2-chlorobenzophenone to the sodium borohydride is 1:0.6-0.7,
preferably, the molar mass ratio of the 2-chlorobenzophenone to the sodium borohydride is 1: 0.6;
B. the temperature T1 is-10 to 10 ℃,
preferably, the temperature T1 is 0 ℃;
C. the temperature is slowly increased to the room temperature;
D. the reaction time t1 is 2-4 h.
4. The method of claim 1, wherein step (1) further satisfies one or more of the following conditions:
E. the first solvent is methanol;
F. the extractant for extraction is ethyl acetate;
G. the drying agent is anhydrous sodium sulfate.
5. The method of claim 1, wherein step (2) satisfies one or more of the following conditions:
H. the molar mass ratio of the compound a to the concentrated hydrochloric acid is 1:5-6,
preferably, the molar mass ratio of the compound a to the concentrated hydrochloric acid is 1: 5;
I. the temperature T2 is 40-50 ℃;
J. the reaction time t2 is 2-4 h.
6. The method of claim 1, wherein step (2) further satisfies one or more of the following conditions:
K. the second solvent is 1, 4-dioxane;
l, the extractant for extraction is ethyl acetate;
m. the organic layer was washed with brine;
the drying is drying with anhydrous sodium sulfate.
7. The method of claim 1, wherein step (3) satisfies one or more of the following conditions:
o. the molar mass ratio of the compound b, potassium carbonate and 1- (2-hydroxyethyl) piperazine is 1:2-3:1-2,
preferably, the molar mass ratio of the compound b, potassium carbonate and 1- (2-hydroxyethyl) piperazine is 1:2: 1;
p. the temperature T3 is 80-90 ℃;
q. the reaction time t3 is 8-12 h.
8. The method for preparing cetirizine impurity C according to claim 1, wherein the solvent three in step (3) is acetone or acetonitrile.
9. The process for the preparation of cetirizine impurity C according to claim 1, characterized in that said step (4) satisfies one or more of the following conditions:
r, the molar mass ratio of the compound c to tetrabutylammonium chloride to tert-butyl bromoacetate is 1:0.4-0.5:2-3,
preferably, the molar mass ratio of the compound c to the tetrabutylammonium chloride to the tert-butyl bromoacetate is 1:0.5: 2;
s. the temperature T4 is room temperature;
t. the reaction time t4 is 6-10 h;
u. the silica gel column was washed with a mixture of dichloromethane and methanol at a molar ratio of 100: 1.
10. The process for the preparation of cetirizine impurity C according to claim 1, characterized in that said step (5) satisfies one or more of the following conditions:
v. the temperature T5 is room temperature;
w, the reaction time t5 is 3-4 h;
x, the stirring time is 1-2 h;
y. the washing detergent is ethyl acetate.
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