CN114478438A - Semicarbazide analogue compound, preparation method and application - Google Patents
Semicarbazide analogue compound, preparation method and application Download PDFInfo
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- -1 Semicarbazide analogue compound Chemical class 0.000 title claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 33
- 229940125782 compound 2 Drugs 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
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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
- C07D295/12—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 or doubly bound nitrogen atoms
- C07D295/135—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention relates to the technical field of medicine production, in particular to a semicarbazide analogue compound, a preparation method and application. The compound 1 and the compound 2 are adopted to react and synthesize the target compound in the presence of a catalyst and organic weak base. The preparation method is simple, the synthetic route is short, the method is economical and reliable, the target compound, namely the semicarbazide analogue compound 3, is obtained in one step, and the finally obtained product is higher in purity.
Description
Technical Field
The invention relates to the technical field of medicine production, in particular to a semicarbazide analogue compound, a preparation method and application.
Background
Posaconazole, english name: posaconazole. The chemical name of the compound is 4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazol-1-ylmethyl) oxolane-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazol-3-one, and the structure is shown as the following formula 1.
Posaconazole was developed by the company pionbauy, germany (now merck) and was first approved for sale in ireland 10 months in 2005. Posaconazole oral suspension (specification: 40mg/ml) was approved by the US FDA at 2006, 9 months; the US FDA successively approved the posaconazole sustained-release tablets (specification: 100 mg/tablet) and the injection (specification: 0.3g/16.7ml) from 11 months in 2013 to 3 months in 2014. Has been approved in 70 countries and regions of the world and is marketed in 40 countries and regions of the United states, European Union, etc. Is a second generation broad spectrum triazole antifungal drug for preventing invasive fungal infection, is suitable for patients with increased risk of invasive aspergillus and candida infection caused by severe immunodeficiency at the age of 13 and above the age of 13, and comprises the prevention and treatment of the invasive fungal infection of patients with graft-versus-host disease (GVHD) after Hematopoietic Stem Cell Transplantation (HSCT) or patients with hematologic malignancy with long-term neutropenia caused by chemotherapy. Due to the characteristics of high efficiency and low toxicity and wide clinical application range, the method provides a selection space for treating clinical invasive fungal infection.
The quality of posaconazole as a drug for people on the market needs to be strictly controlled. In view of the safety of human administration, any one of the active ingredients (API) of a pharmaceutical product requires a very low limit for the identification of pharmacologically toxicologically-relevant impurities established by the national and international authorities of the relevant authorities before commercialization. Since impurities generally have no therapeutic effect but have a certain harmful effect on human body functions, the impurities must be effectively controlled in a drug or an active ingredient (API). It is known that impurities are classified into general impurities and special impurities from the aspect of sources, and the impurities in the posaconazole active ingredient (API) are probably derived from self-synthesis and degradation processes. Mainly comprises unreacted raw materials; impurities originally existing in raw materials and derivatives thereof, synthetic byproducts, degradation products and the like, impurities synthesized by multi-site reaction of main reaction and the like.
Impurities in the medicine may bring adverse reactions to human bodies, causing serious consequences. It is therefore necessary and necessary to understand the chemical structure of the impurities and their pharmacological and toxicological properties. This requires the preparation of higher purity impurity controls. Generally, in chemical synthesis of API, separation, purification, and the like of target impurities are extremely difficult due to complicated components, by-products, degradation products, and the like. Therefore, it is very important to efficiently and easily prepare a high-purity impurity reference substance and find a feasible path.
Disclosure of Invention
The invention aims to provide a semicarbazide analogue compound, a preparation method and application, in particular to a high-efficiency and simple method for preparing a posaconazole impurity reference substance, and a reliable and stable impurity synthesis process is established. The process has short synthetic route, can obtain the semicarbazide analogue (compound 3) as the target impurity by only one step, has no safety problem, and has simple and easy separation and purification means, and is economic and reliable. The synthetic route is as follows:
in order to achieve the above purpose, the invention specifically adopts the following technical scheme
A semicarbazide analog compound, said compound having the structure:
the preparation method of the compound comprises the following steps of reacting a compound 1 and a compound 2 in the presence of a catalyst and an organic weak base to synthesize a target compound, namely a compound 3:
the catalyst is DMAP. Wherein compound 1 is a hydrazonium succinate analog.
Preferably, the organic weak base is selected from triethylamine, diethylamine, imidazole, pyridine or aniline.
Preferably, the preparation method comprises the following specific steps:
(1) dissolving the compound 1 and the compound 2 in an organic solvent, adding a catalyst and organic weak base, stirring and dissolving;
(2) continuously stirring the solution obtained in the step (1) at 25-95 ℃ for reaction;
(3) after the reaction is finished, dripping the reaction liquid obtained in the step (2) into water, and adding an organic solvent for extraction;
(4) concentrating the organic phase obtained in the step (3) under reduced pressure to obtain a colored oily substance;
(5) and (4) carrying out column chromatography purification on the oily substance obtained in the step (4) to obtain the target compound.
Preferably, the organic solvent in step (1) is selected from DMF, DMAC, DMSO, toluene or NMP.
Preferably, the reaction temperature in the step (2) is 50-80 ℃.
Preferably, the organic solvent for extraction in step (3) is selected from ethyl acetate, dichloromethane or methyl tertiary butyl ether.
Preferably, the column chromatography eluent in the step (5) is selected from petroleum ether, ethyl acetate 1:1 or 1: 2; or n-hexane ethyl acetate 1:1 or 1: 2; or dichloromethane: methanol 20: 1.
Preferably, the molar ratio of the catalyst to the compound 1 is 0.1-5: 1; the molar ratio of the compound 2 to the compound 1 is 1.1-2.5; the molar ratio of the organic weak base to the compound 1 is 1-8: 1.
Preferably, the molar ratio of the catalyst to the compound 1 is 0.5-2: 1; the molar ratio of the compound 2 to the compound 1 is 1.2-2.0; the molar ratio of the organic weak base to the compound 1 is 1.5-3.5: 1.
The application of the compound in preparing a reference substance of posaconazole intermediate impurities or preparing a reference substance of posaconazole impurities.
Has the advantages that:
the preparation method is efficient, simple, reliable and stable;
the process has short synthetic route, and the semicarbazide analogue (compound 3) as the target impurity can be obtained by only one step;
the process of the invention has no safety problem, and the separation and purification means are simple and easy to implement, economic and reliable;
the product prepared by the method has higher purity.
Drawings
FIG. 1 shows nuclear magnetism of synthesized impurity (Compound 3) of example 71H-NMR spectrum.
FIG. 2 is a MS spectrum of the synthesized impurity of example 7 (Compound 3).
FIG. 3 synthesis of impurities from example 9Nuclear magnetism of (Compound 3)1H-NMR spectrum.
FIG. 4 is a MS spectrum of the synthesized impurity (Compound 3) of example 9.
FIG. 5 is an HPLC chromatogram of the synthesized impurity of example 9 (Compound 3).
FIG. 6 nuclear magnetism of synthesized impurity (Compound 3) of example 101H-NMR spectrum.
FIG. 7 is a MS spectrum of the synthesized impurity (Compound 3) of example 10.
FIG. 8 HPLC chart of intermediate compound 5 obtained by posaconazole synthesis process
FIG. 9 intermediate Compound 5 and HPLC plot after labeling
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. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. 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.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The relative arrangement of the components and steps, the numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless specifically stated otherwise. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.
The present invention is described in detail below with reference to examples to facilitate the understanding of the present invention by those skilled in the art, and the following examples are all consistent with the system for the synthesis of posaconazole as the impurity is produced in the process.
Some of the posaconazole impurities have been reported in the literature (Structural characterization of imprints and degradation products 164-177), but the impurity (Compound 3) has not been reported. The impurity (compound 3) is found in a synthesis system of one intermediate (compound 5) in the posaconazole synthesis process, and the synthesis route of the intermediate is as follows:
from the scheme, it is seen that compound 4 (hydrazinium oxalate analogue) and compound 2 synthesize posaconazole intermediate (compound 5) under the catalyst, and the HPLC diagram of the intermediate product is shown in fig. 8.
In the spectrum, RT-14.208 min (RRT-1.0) is compound 5, RT-15.883 min (RRT-1.12) is unknown impurity, and the content thereof is found to exceed the limit of I (standard is less than or equal to 0.10%); for the unknown impurity, we guess that it should be generated in the reaction and not introduced by the subsequent treatment, and the impurity generated in the system is not generated by the side reaction which is not the product degradation or generated by the impurity in the raw material, and compound 5 is stable in the system by stability test, so the impurity is probably a byproduct (compound 3) generated by the reaction with the impurity in the raw material, and we inquired that compound 1 is the starting raw material, and the COA of the raw material manufacturer shows that one of the most main impurities (compound 1) in the raw material is similar to the structure of compound 4, and we guess that the unknown impurity in compound 5 should be compound 3 generated by the reaction of compound 1 and compound 2. In this regard, we designed an experiment, in which compound 1 and compound 2 were used to synthesize compound 3 in the same reaction system as the posaconazole intermediate, and the objective of determining whether the impurity (RRT ═ 1.12) in the final product of posaconazole intermediate (compound 5) and compound 3 were the same compound was achieved by a spiking experiment. The pure compound 5 is obtained by a separation method, and the chemical structure of the compound is determined by nuclear magnetic mass spectrometry. We performed a spiking experiment with compound 3, which is to add compound 3 to compound 5 containing an unknown impurity (RRT ═ 1.12) to give a mixture, which was examined by HPLC to verify whether the unknown impurity was consistent with the position of the compound 3 peak. If the two are consistent, the structure of the unknown impurity (RRT ═ 1.12) in the compound 5 can be shown to be the compound 3, and the opposite is not. For this, we measured both the intermediate (compound 5) containing the unknown impurity (RRT ═ 1.12) and the HPLC profile after labeling, which is shown in fig. 9.
From the labeling experiment and the HPLC spectrum of compound 5, it can be seen that the content of the unknown impurity (RRT ═ 1.12) is increased significantly after the labeling, and the peak position of compound 3 completely coincides with the unknown impurity, thereby confirming that the chemical structure of the unknown impurity in compound 5 is compound 3. The discovery of the impurities plays a key positive role in the perfection of the research on the posaconazole impurities and the control of adverse drug reactions.
Example 1
Adding 3.0g of compound 1, 2.27g of compound 2, 0.32g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 24 hours at 25 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, concentrating under reduced pressure to obtain a dark brown oily liquid, and purifying by column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.24g of light yellow solid (compound 3), wherein the yield is 8.9%, and the purity is 98.1%.
Example 2
Adding 3.0g of compound 1, 2.27g of compound 2, 0.32g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 24 hours at 45 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, concentrating under reduced pressure to obtain a dark brown oily liquid, and purifying by column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.33g of light yellow solid (compound 3), wherein the yield is 12.5%, and the purity is 98.5%.
Example 3
Adding 3.0g of compound 1, 2.27g of compound 2, 0.32g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting at 70 ℃ for 24 hours, dripping the reaction solution into 30ml of water, extracting by 100ml of dichloromethane, concentrating under reduced pressure to obtain a dark brown oily liquid, and purifying by column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.55g of light yellow solid (compound 3), wherein the yield is 20.5%, and the purity is 98.6%.
Example 4
Adding 3.0g of compound 1, 2.27g of compound 2, 0.32g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting at 95 ℃ for 24 hours, dripping the reaction solution into 30ml of water, extracting by 100ml of dichloromethane, concentrating under reduced pressure to obtain a dark brown oily liquid, and purifying by column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.53g of light yellow solid (compound 3), wherein the yield is 20.1%, and the purity is 98.5%.
Example 5
Adding 3.0g of compound 1, 2.27g of compound 2, 0.32g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 8 hours at 70 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, concentrating under reduced pressure to obtain dark brown oily liquid, and purifying by column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.54g of light yellow solid (compound 3), wherein the yield is 20.3%, and the purity is 98.6%.
Example 6
Adding 3.0g of compound 1, 2.27g of compound 2, 0.32g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 8 hours at 70 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, concentrating under reduced pressure to obtain dark brown oily liquid, and purifying by column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.54g of light yellow solid (compound 3), wherein the yield is 20.3%, and the purity is 98.6%.
Example 7
Adding 3.0g of compound 1, 3.09g of compound 2, 0.65g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 8 hours at 70 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, distilling under reduced pressure to obtain a dark brown oily liquid, and performing column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.67g of light yellow solid (compound 3), wherein the yield is 25.3%, and the purity is 98.7%.
1H NMR(400MHz,DMSO)δ8.88(s,1H),8.86(s,1H),7.42(d,J＝8.9Hz,2H),7.34(t,J＝7.4Hz,5H),6.92(d,J＝9.0Hz,2H),6.87(d,J＝8.9Hz,2H),6.70(d,J＝8.9Hz,2H),4.62(d,J＝11.8Hz,1H),4.40(d,J＝11.8Hz,1H),4.29(s,2H),4.23(dd,J＝10.6,5.3Hz,1H),3.76–3.68(m,1H),3.19(d,J＝5.0Hz,4H),3.12(d,J＝4.4Hz,4H),1.78(d,J＝10.6Hz,1H),1.55(dd,J＝7.0,2.2Hz,1H),1.18(d,J＝6.2Hz,3H),0.83(t,J＝7.3Hz,3H).ESI+-MS[M+H]504.6,[M+Na]526.6.
Example 8
Adding 3.0g of compound 1, 3.09g of compound 2, 1.03g of DMAP, 0.54g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 8 hours at 70 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, distilling under reduced pressure to obtain a dark brown oily liquid, and performing column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.66g of a light yellow solid (compound 3), wherein the yield is 25.1%, and the purity is 98.7%.
Example 9
Adding 3.0g of compound 1, 3.09g of compound 2, 0.65g of DMAP, 0.79g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 8 hours at 70 ℃, dripping the reaction solution into 30ml of water, extracting 100ml of dichloromethane, distilling under reduced pressure to obtain dark brown oily liquid, and performing column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.81g of light yellow solid (compound 3) with the yield of 30.3 percent, wherein the nuclear magnetic hydrogen spectrum of the compound is shown in figure 1, the MS spectrum is shown in figure 2, the HPLC is shown in figure 3, and the purity of the product is 99.2 percent.
1H NMR(400MHz,DMSO)δ9.02(s,1H),8.89(s,1H),7.42(d,J＝9.0Hz,2H),7.36–7.27(m,5H),6.91(d,J＝9.1Hz,2H),6.88–6.84(m,2H),6.72(dd,J＝9.6,2.8Hz,2H),4.61(d,J＝11.8Hz,1H),4.39(d,J＝11.8Hz,1H),4.30(s,2H),4.26–4.20(m,1H),3.76–3.68(m,1H),3.19(dd,J＝6.4,2.9Hz,4H),3.13–3.09(m,4H),1.78(s,1H),1.54(dd,J＝7.0,2.2Hz,1H),1.18(d,J＝6.2Hz,3H),0.82(t,J＝7.3Hz,3H).ESI+-MS[M+H]504.6,[M+Na]526.6.
Example 10
Adding 3.0g of compound 1, 3.09g of compound 2, 0.65g of DMAP, 1.08g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting for 8 hours at 70 ℃, dripping the reaction liquid into 30ml of water, extracting by 100ml of dichloromethane, distilling under reduced pressure to obtain dark brown oily liquid, and performing column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.80g of light yellow solid (compound 3), wherein the yield is 30.1% and the purity is 99.1%.
1H NMR(400MHz,DMSO)δ9.00(s,1H),8.48(s,1H),7.40–7.34(m,4H),7.33–7.25(m,3H),6.93–6.81(m,4H),6.76–6.68(m,2H),4.76(s,1H),4.60(d,J＝11.8Hz,1H),4.46(d,J＝11.8Hz,1H),3.70–3.55(m,1H),3.18(dd,J＝6.5,2.8Hz,4H),3.14–3.08(m,4H),2.72(s,2H),1.94(s,1H),1.61–1.50(m,1H),1.19(d,J＝6.3Hz,3H),0.95(t,J＝7.4Hz,3H).ESI+-MS[M+H]504.6,[M+Na]526.6.
Example 11
Adding 3.0g of compound 1, 3.09g of compound 2, 0.65g of DMAP, 0.79g of imidazole and 3ml of DMSO in sequence, stirring and dissolving, reacting at 70 ℃ for 6 hours, dripping the reaction solution into 30ml of water, extracting by 100ml of dichloromethane, distilling under reduced pressure to obtain a dark brown oily liquid, and performing column chromatography (using a 18 x 160mm glass chromatographic column, 300-400 meshes of silica gel and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent) for 3 times to obtain 0.79g of a light yellow solid (compound 3), wherein the yield is 29.9% and the purity is 99.1%.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (10)
1. A semicarbazide analog compound characterized by the structure:
2. a process for producing a compound according to claim 1, characterized by reacting a compound 1 with a compound 2 in the presence of a catalyst and a weak organic base to synthesize a compound according to claim 1:
the catalyst is DMAP.
3. The method according to claim 2, wherein the weak organic base is triethylamine, diethylamine, imidazole, pyridine or aniline.
4. The preparation method according to claim 2, comprising the following specific steps:
(1) dissolving the compound 1 and the compound 2 in an organic solvent, adding a catalyst and organic weak base, stirring and dissolving;
(2) continuously stirring the solution obtained in the step (1) at 25-95 ℃ for reaction;
(3) after the reaction is finished, dripping the reaction liquid obtained in the step (2) into water, and adding an organic solvent for extraction;
(4) concentrating the organic phase obtained in the step (3) under reduced pressure to obtain a colored oily substance;
(5) and (4) carrying out column chromatography purification on the oily substance obtained in the step (4) to obtain the target compound.
5. The method according to claim 4, wherein the organic solvent in step (1) is DMF, DMAC, DMSO, toluene or NMP.
6. The process according to claim 4, wherein the organic solvent for extraction in the step (3) is selected from ethyl acetate, methylene chloride and methyl tert-butyl ether.
7. The process according to claim 4, wherein the eluent for column chromatography in step (5) is selected from the group consisting of petroleum ether and ethyl acetate 1:1 or 1: 2; or n-hexane and ethyl acetate are 1:1 or 1: 2; or dichloromethane to methanol at 20: 1.
8. The process according to any one of claims 1 to 7, wherein the molar ratio of the amount of the catalyst to the compound 1 is 0.1 to 5: 1; the molar ratio of the compound 2 to the compound 1 is 1.1-2.5; the molar ratio of the organic weak base to the compound 1 is 1-8: 1.
9. The preparation method according to claim 8, wherein the molar ratio of the catalyst to the compound 1 is 0.5-2: 1; the molar ratio of the compound 2 to the compound 1 is 1.2-2.0; the molar ratio of the organic weak base to the compound 1 is 1.5-3.5: 1.
10. Use of a compound of claim 1 for the preparation of a posaconazole intermediate or a reference posaconazole impurity.
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| CN105622591A (en) * | 2014-11-06 | 2016-06-01 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of novel triazole antifungal drug |
| CN108976218A (en) * | 2018-09-07 | 2018-12-11 | 成都自豪药业有限公司 | Posaconazole succinyl adduct impurity and its preparation method and application |
| CN110927262A (en) * | 2018-09-20 | 2020-03-27 | 河南天晟泰丰医药科技有限公司 | Method for detecting initial material impurities in posaconazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622591A (en) * | 2014-11-06 | 2016-06-01 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of novel triazole antifungal drug |
| CN108976218A (en) * | 2018-09-07 | 2018-12-11 | 成都自豪药业有限公司 | Posaconazole succinyl adduct impurity and its preparation method and application |
| CN110927262A (en) * | 2018-09-20 | 2020-03-27 | 河南天晟泰丰医药科技有限公司 | Method for detecting initial material impurities in posaconazole |
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