CN112062754A - Preparation method of intermediate for synthesizing Dorzagliatin - Google Patents
Preparation method of intermediate for synthesizing Dorzagliatin Download PDFInfo
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- CN112062754A CN112062754A CN202011012899.0A CN202011012899A CN112062754A CN 112062754 A CN112062754 A CN 112062754A CN 202011012899 A CN202011012899 A CN 202011012899A CN 112062754 A CN112062754 A CN 112062754A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention provides a preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia, which belongs to the technical field of organic synthesis application and is designed with a route without a protecting group from simple and easily-obtained raw materials to obtain a target product (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia. The invention has the technical effects that: the reaction flow is shortened, the types and the dosage of reagents are reduced, and the protection and deprotection of amino groups are avoided.
Description
Technical Field
The invention belongs to the technical field of organic synthesis application, and particularly relates to a method for rapidly synthesizing and preparing (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia in a multi-step reaction.
Background
(R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II) is a very important medical intermediate for synthesizing Dorzagliatin. Dorzagliatin is a novel medicine for treating type 2 diabetes mellitus, and (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II) is an essential intermediate in the synthetic process of the medicine, and along with the steady promotion of new Dorzagliatin medicines to the market, the demand of the chiral intermediate in the market is required to be rapidly increased.
The main production method of the key chiral intermediate is shown as follows: reducing nitro in 3-nitro-1H-pyrazole substrate into amino, protecting free amino, carrying out N-alkylation reaction with (R) - (-) -2, 3-O-isopropylidene glycerol-OH derivative active intermediate, and deprotecting to obtain the final product. The synthetic route needs to be subjected to an N-protection process, so that route steps are added, and the cost is increased. The synthesis of N-protected substrate iv is reported: in the patent US2013203802, 1H-pyrazole-3-ammonia is protected by acetic anhydride, and in WO2017040757, N-acetyl-1H-pyrazole-3-ammonia is obtained by an N- (1-benzyl-1H-pyrazole-3-yl) acetamide debenzylation method; the protection of the N-benzoyl group of 1H-pyrazol-3-amine is reported in the patent US 6118008; in addition, WO2009106209, US2012095064, mention the phthalimide protection strategy of 1H-pyrazole-3-ammonia with phthalic anhydride.
Although some methods for preparing (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia are disclosed at present, N protection and deprotection processes are needed, the production cost is high, and a new process route is still needed to be developed to further reduce the production cost of the medicine.
Disclosure of Invention
Aiming at the defects of the prior art, the invention designs a process which adopts chiral source introduction and does not need free ammonia N protection, and the process is successfully applied to the preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II).
The invention provides a preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia, which is characterized in that a route without a protecting group is designed from simple and easily-obtained raw materials to obtain a target product (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia.
The invention is realized by the following technical scheme:
a preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II), taking 3-nitro-1H-pyrazole as a raw material, heating to 10-80 ℃ to react with (S) - (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane for 0.5-20H under an alkaline condition to obtain an intermediate I product, and then, carrying out a closed reaction on the intermediate I product in methanol at the hydrogen pressure of 0.2-3 MPa and the temperature of 10-80 ℃ for 3-20H to obtain a (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II) product. The preparation method effectively avoids the step of protecting group on N required in the synthesis of the product, improves the economy of the route and reduces the cost.
As a further description of the technical scheme of the invention, the preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (ii) specifically comprises the following steps:
s1, preparing an intermediate (R) -I: mixing 3-nitro-1H-pyrazole (1), alkali and a reaction solution in a reaction bottle, stirring at room temperature to promote the uniform reaction, dissolving and diluting (S) - (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane ((S) -2), dropwise adding into the reaction bottle, heating to 10-80 ℃ after dropwise adding, stirring for reaction, preferably at 45-80 ℃, removing ethanol by reduced pressure distillation after the reaction is finished, adding water into residues for dilution, then extracting by adopting dichloromethane, sequentially washing obtained organic phases with water, washing with saturated sodium chloride and salt water, and removing dichloromethane by reduced pressure concentration to obtain a crude oily substance; purifying the crude product by silica gel column chromatography to obtain an N-alkylated intermediate (R) -I;
s2, reducing nitro to obtain a target product: adding an intermediate (R) -I, a reaction solvent and a nitro reduction system into an autoclave, firstly replacing the autoclave with nitrogen and then hydrogen, then filling hydrogen to adjust the pressure to 0.2-3 MPa, adjusting the reaction temperature to 10-80 ℃, reducing nitro in a palladium carbon-hydrogen system, filtering the reaction result after the reaction is finished, removing the catalyst (the nitro reduction system), and then removing the reaction solvent to obtain the target product (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia.
In the present invention, the synthetic route of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine is as follows:
as a further description of the technical scheme of the invention, in S1, the reaction molar ratio of the raw material 1 to the (S) -2 is (1.05-1.25): 1.
as a further description of the technical means of the present invention, in S1, the base may be sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium phosphate, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium tert-amylate, 1, 8-diazabicycloundecen-7-ene (DBU), 1, 4-diazabicyclo [2.2.2] octane (DABCO), lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, or the like.
As a further description of the technical solution of the present invention, the reaction solvent used in S1 is one or a mixture of any combination of ethanol, methanol, isopropanol, tert-butanol, acetone, acetonitrile, dichloromethane, N-dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide.
As a further description of the technical scheme of the invention, in S2, the reaction solvent is one or any kind of mixed solvent in proportion of methanol, ethanol, isopropanol, acetic acid, dichloromethane, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and toluene.
As a further description of the technical scheme of the invention, in S2, the nitro reduction system is Pd/C-H2Pd/C-ammonium formate, Pt/C-H2Lithium aluminium hydride, Raney-Ni (Raney nickel), iron powder-ammonium chloride or hydrochloric acid, zinc powder-acetic acid, sodium sulfide-polysulfide, hydrazine hydrate or any combination of reducing agents.
Based on the technical scheme, the invention has the technical effects that:
(1) the invention provides a preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II), which adopts a chiral source method to efficiently obtain an optically pure target configuration intermediate and a final product;
(2) according to the preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyridine-3-ammonia (II), the nitro is directly subjected to N-alkylation reaction under the condition of retaining the nitro, and finally the nitro is reduced, so that the complicated steps of amino protection and deprotection are avoided, the reaction flow is shortened, the types and the dosage of reagents are reduced, and the cost advantage is obvious.
(3) The invention provides a preparation method of (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II), which comprises the steps of directly introducing a chiral center into a commercially available chiral building block of (S) - (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane ((S) -2), building an intermediate (R) -I [ (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -3-nitro-1H-pyrazole ] through nucleophilic substitution N-alkylation reaction, the final product is obtained by reducing the nitro group in one step, the steps are shortened, and the operation is simple and convenient.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the specific embodiments illustrated. The invention provides a preferred embodiment. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Example 1
Preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine
The first step is as follows: intermediate (R) -I preparation:
under the protection of nitrogen, 3-nitro-1H-pyrazole (1) (100.00g,0.884mol), ethanol (1.0L) and sodium carbonate (133.90g, 1.26mol) are sequentially added into a 3L reaction bottle, and the system is stirred for 0.5H at room temperature; (S) - (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane ((S) -2) (126.84g, 0.842mol) was dissolved and diluted with 634ml of ethanol and then added dropwise to the reaction flask. After the dropwise addition, the temperature is raised to 50 ℃ and the reaction is stirred for 5 hours. Ethanol was distilled off under reduced pressure, and the residue was diluted with (1.0L) of water and then extracted twice with dichloromethane (500ml × 2); the organic phase was washed with water and then with saturated sodium chloride brine. Concentrating under reduced pressure to remove dichloromethane to obtain crude oily substance; the crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixed system) to give 166.5g of a pale yellow oily product, with a yield of 87% and an ee value of 98% or more.
The second step is that: reducing nitro to obtain target product
A2L autoclave was charged with (R) -I substrate (150g, 0.66mol), methanol (750mL), Pd/C (0.75g, 0.5% W/W), and the mixture was subjected to nitrogen substitution three times, then hydrogen substitution three times, under a hydrogen-charging pressure of 2.0MPa, at a temperature of 50 ℃ for reaction for 8 hours. Filtering, filtering to remove Pd/C catalyst, concentrating the filtrate to remove methanol to obtain 123.70g of light yellow oily matter, wherein the yield is 95%, and the ee value is more than or equal to 98%.
Example 2
Preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine by Raney-Ni reduction system
The first step is the same as in example 1.
The second step is that: reduction of nitro groups by Rany-Ni
The intermediate (R) -I (150g, 0.66mol) obtained in the first step was charged into a 2L reactor, and ethanol (1.2L) was added thereto and stirred, followed by adding Rany-Ni (75g) and stirring at room temperature for reaction for 15 hours. Filtering, filtering to remove the solid catalyst, and concentrating the filtrate to dryness to obtain 106.77g of light yellow oily substance with yield of 82% and ee value of more than or equal to 97%.
Example 3
Preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine by hydrazine hydrate system
The first step is the same as in example 1.
The second step is that: A2L reaction flask was charged with intermediate (R) -I (150g, 0.66mol), ferric trichloride (528mg, 3.3mmol), and ethanol (1.2L), stirred, charged with hydrazine hydrate (39.5g, 0.79mol), and heated to reflux for 6 h. Ethanol was removed by concentration under reduced pressure, the residue was diluted with 750ml of water and extracted twice with ethyl acetate (250 ml. times.2). The organic phase was washed with water and then with saturated brine. The ethyl acetate is removed by concentration to obtain 110.7g of crude light yellow oily substance, the yield is 85 percent, and the ee value is more than or equal to 97 percent.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A preparation method of an intermediate for synthesizing Dorzagliatin is characterized by comprising the following steps:
s1: reacting 3-nitro-1H-pyrazole (1) with (S) - (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane ((S) -2) under the condition of alkali promotion to obtain an N-alkylated intermediate (R) -I;
s2: the intermediate (R) -I is subjected to nitro reduction in a palladium-carbon-hydrogen reduction system to obtain a target product (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia.
2. The process for preparing intermediates in the synthesis of Dorzagliatin according to claim 1, wherein the molar ratio of 3-nitro-1H-pyrazole (1) to (S) - (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane ((S) -2) in step S1 is 1.05 to 1.25: 1.
3. the process of claim 1, wherein the base in S1 is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium phosphate, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium tert-amylate, 1, 8-diazabicycloundecan-7-ene, 1, 4-diazabicyclo [2.2.2] octane, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and/or lithium diisopropylamide.
4. The process of claim 1, wherein the reaction solvent in S1 is at least one of ethanol, methanol, isopropanol, tert-butanol, acetone, acetonitrile, dichloromethane, N-dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide.
5. The process of claim 1, wherein the solvent used in the step of S2 is at least one selected from the group consisting of methanol, ethanol, isopropanol, acetic acid, dichloromethane, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.
6. The process of claim 1, wherein the nitroreductase system in S2 is Pd/C-H2Pd/C-ammonium formate, Pt/C-H2, lithium aluminum hydride, Raney-Ni/H2One or more of iron powder-ammonium chloride or hydrochloric acid, zinc powder-acetic acid, sodium sulfide-polysulfide and hydrazine hydrate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008156757A1 (en) * | 2007-06-19 | 2008-12-24 | Takeda Pharmaceutical Company Limited | Indazole compounds for activating glucokinase |
| CN101918363A (en) * | 2008-01-18 | 2010-12-15 | 安斯泰来制药株式会社 | Phenyl acetamide derivative |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008156757A1 (en) * | 2007-06-19 | 2008-12-24 | Takeda Pharmaceutical Company Limited | Indazole compounds for activating glucokinase |
| CN101918363A (en) * | 2008-01-18 | 2010-12-15 | 安斯泰来制药株式会社 | Phenyl acetamide derivative |
Non-Patent Citations (1)
| Title |
|---|
| SPASSOVA, MARIA K.，ET AL.: "Ribonucleosides of 3-amino- and 3,5-diaminopyrazole-4-carboxylic acid and their open-chain analogs: synthesis and reactions", 《COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS 》 * |
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