CN112225761A - Pyrimidotriazole and synthetic method thereof - Google Patents

Pyrimidotriazole and synthetic method thereof Download PDF

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CN112225761A
CN112225761A CN202011487393.5A CN202011487393A CN112225761A CN 112225761 A CN112225761 A CN 112225761A CN 202011487393 A CN202011487393 A CN 202011487393A CN 112225761 A CN112225761 A CN 112225761A
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structural formula
reaction
compound shown
carboxylate
pyrimidotriazole
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CN112225761B (en
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鲍甫义
袁仁涛
马丁来
冯力
佟有恩
李小波
潘永利
叶小新
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Guoqing Biomedical Shanghai Co ltd
Nanjing Yiyuan Biomedical Research Institute Co ltd
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Nanjing Yiyuan Biomedical Research Institute Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Abstract

The invention discloses a synthesis method of pyrimidotriazole, which comprises the following steps: step one, reacting 4- (O- (2, 4, 6-triisopropyl) benzenesulfonyl) -uridine with N-tert-butyloxycarbonyl hydrazine to obtain a compound shown as a structural formula II; and step two, dissolving the compound shown in the structural formula two in a formic acid aqueous solution, stirring for 8-12h at room temperature, concentrating the reaction solution after the reaction is finished, and performing column chromatography separation to obtain the compound shown in the structural formula one. The method disclosed by the invention can be carried out at room temperature without using corrosive reagents, no corrosive gas is generated in the reaction process, the requirement on equipment is not high, and the method is a meaningful method for synthesizing pyrimidotriazole.

Description

Pyrimidotriazole and synthetic method thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of pyrimidotriazole.
Background
The synthesis of the triazole pyrimidine compound is widely concerned as a medicine for treating hyperthyroidism. The synthesis methods reported in the literature can be roughly divided into the following types:
1. uracil and POCl3/PCl54-chloro-pyrimidine is obtained by reaction, N-aminocytosine is obtained by reaction of the 4-chloro-pyrimidine and hydrazine, and the final product is obtained by reaction of the N-aminocytosine and trimethyl orthoformate. [ Molecules 2018, 23, 2913]Such processes require the use of POCl3/PCl5And the like, and a large amount of hydrogen chloride gas is released in the reaction process, so that the requirement on equipment is high. In addition, trimethyl orthoformate is needed to be used as a reactant and a solvent in the last step of ring closure reaction, more raw materials are wasted, and the method using trifluoroacetic acid as a catalyst is also providedJ. Chem. Soc., Perkin Trans. 1, 2000, 33–42]Trifluoroacetic acid, however, is also more corrosive to equipment, limiting the utility of such processes. (Scheme 1)
Figure 224331DEST_PATH_IMAGE001
2. 4-oxygen of the pyrimidine compound is converted into sulfur, then the sulfur reacts with hydrazine hydrate to obtain an N-aminopyrimidine compound, and the N-aminopyrimidine compound reacts with trimethyl orthoformate to obtain a final product. [ chem. Commun, 1999, 1461-1462 ] this method needs to use sulfuration reagent, which will generate foul smell in the experiment and post-treatment process, the reaction between hydrazine hydrate and thiopyrimidine needs to be carried out under reflux condition, which has danger of explosion, finally the ring-closing reaction needs to use trifluoroacetic acid as solvent, which corrodes the equipment, and has high requirement for equipment. There is also a method of directly using trimethyl orthoformate without adding trifluoroacetic acid. J. chem. Soc., Perkin Trans. 1, 1999, 3117-. (Scheme 2)
Figure 203788DEST_PATH_IMAGE002
。
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.
Disclosure of Invention
The invention aims to provide a pyrimidine triazole synthesis process which is mild in reaction condition and simple, so that the defects in the prior art are overcome.
In order to realize the purpose, the invention provides a synthesis method of pyrimidotriazole, which comprises the following steps: step one, reacting 4- (O- (2, 4, 6-triisopropyl) benzenesulfonyl) -uridine with N-tert-butyloxycarbonyl hydrazine to obtain a compound shown as a structural formula II,
Figure 983526DEST_PATH_IMAGE003
structural formula two, wherein R1, R2 are the same or different hydrocarbyl groups, R3 can be a carboxylate or a phosphate group;
step two, dissolving the compound shown in the structural formula two in a formic acid aqueous solution, stirring for 8-12h at room temperature, concentrating reaction liquid after the reaction is finished, and performing column chromatography separation to obtain the compound shown in the structural formula one,
Figure 191784DEST_PATH_IMAGE004
structural formula one, wherein R can be a carboxylate or a phosphate group.
The method disclosed by the invention can be carried out at room temperature without using corrosive reagents, no corrosive gas is generated in the reaction process, the requirement on equipment is not high, and the method is a meaningful method for synthesizing pyrimidotriazole. (Scheme 3)
Figure 68473DEST_PATH_IMAGE005
。
A synthesis method of pyrimidotriazole comprises the following steps: step one, reacting 4- (O- (2, 4, 6-triisopropyl) benzenesulfonyl) -uridine with hydrazine hydrochloride to obtain a compound shown as a structural formula III,
Figure 890936DEST_PATH_IMAGE006
structural formula III, wherein R1, R2 are the same or different hydrocarbyl groups, R3 can be a carboxylate or a phosphate group;
step two, dissolving the compound shown in the structural formula III in a formic acid aqueous solution, stirring for 8-12h at room temperature, concentrating reaction liquid after the reaction is finished, and performing column chromatography separation to obtain the compound shown in the structural formula I,
Figure 487132DEST_PATH_IMAGE007
structural formula one, wherein R can be a carboxylate or a phosphate group.
Preferably, in the above technical solution, the method specifically comprises the following steps: the reaction temperature in the first step is room temperature, and the reaction solvent is acetonitrile or other solvents with the same solubility.
A pyrimidotriazole of the structural formula I or a pharmaceutically acceptable salt thereof:
Figure 686032DEST_PATH_IMAGE008
structural formula one, wherein R can be a carboxylate or a phosphate group.
A pharmaceutically acceptable salt of an N- (N-t-butoxycarbonylimino) cytosine nucleoside of the structural formula:
Figure 417227DEST_PATH_IMAGE009
the structural formula II is shown in the specification, wherein R1 and R2 are the same or different hydrocarbon groups, and R3 can be carboxylic ester or phosphate group.
An N-aminocytosine nucleoside of structural formula iii a pharmaceutically acceptable salt thereof:
Figure 410591DEST_PATH_IMAGE010
structural formula III, wherein R1 and R2 are the same or different hydrocarbyl groups, and R3 can be a carboxylate or a phosphate group.
Compared with the prior art, the invention has the following beneficial effects: the method disclosed by the invention can be carried out at room temperature without using corrosive reagents, no corrosive gas is generated in the reaction process, the requirement on equipment is not high, and the method is a meaningful method for synthesizing pyrimidotriazole.
Description of the drawings:
FIG. 1 shows the product C1Structural spectrogram of (1);
FIG. 2 shows the product C2Structural spectrum of (1).
The specific implementation mode is as follows:
the following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
The synthesis of 4- (O- (2, 4, 6-triisopropyl) benzenesulfonyl) uridine was carried out according to the methods of patents [ WO2019113462A1] and [ WO 2015/200205A 1 ].
Synthesis of 4-bisaminouridine-5' -isobutyrate:
Figure 164921DEST_PATH_IMAGE011
，
at room temperature, Compound A1(5.33 g, 8.6 mmol) is dissolved in acetonitrile (150 mL), triethylamine (2.61 g, 25.8 mmol) and N-tert-butoxycarbonylhydrazine (3.40 g, 25.8 mmol) are added in turn, the mixture is stirred at room temperature for 12h, the reaction solution is concentrated, and the product B is obtained by column chromatography separation1(3.5 g, white solid).
And (3) synthesizing a final product of pyrimidotriazole:
Figure 901932DEST_PATH_IMAGE012
，
compound B1(2.2 g, 4.7 mmol) was dissolved in formic acid (50 mL, 80% v/v), stirred overnight at room temperature, the reaction was concentrated and separated by column chromatography to give product C1(1.2 g, white solid).
1H NMR（400MHz, DMSO-d6）δ：9.28（s，1H）,7.51（d，1H）,6.90（d，1H），5.95（d，1H），5.55（d，1H）5.34（d，1H），4.30-4.28（m，2H），4.19-4.18（m，1H），4.11-4.10（m，1H），4.01-4.00（m，1H），2.63-2.60（m，1H），1.13-1.11（d，6H）。
Synthesis of N-aminocytidine phosphate:
Figure 238367DEST_PATH_IMAGE013
，
at room temperature, Compound A2(2.0 g, 2.3 mmol) is dissolved in acetonitrile (50 mL), triethylamine (707 mg, 7.0 mmol) and hydrazine hydrochloride (479 mg, 7.0 mmol) are added in turn, the mixture is stirred for 12h at room temperature, the reaction solution is concentrated, and the product B is obtained by column chromatography separation2(1 g, white solid).
Synthesis of pyrimidotriazole phosphate:
Figure 668211DEST_PATH_IMAGE014
，
compound B2(0.5 g, 0.7 mmol) was dissolved in aqueous formic acid (20 mL, 80% v/v), stirred overnight at room temperature, the reaction was concentrated and separated by column chromatography to give product C2(0.3 g, white solid).
1H NMR（400MHz, DMSO-d6）δ：9.29（s，1H），7.50（d，1H），6.85（d，1H），5.96（d，1H），5.64-5.57（m，5H），5.38（s，1H），4.31-4.26（m，2H），4.17（s，1H）4.08（s，1H），4.01（s，1H），1.18（s，9H），1.13（s，9H）。
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims (6)

1. The synthesis method of the pyrimidotriazole is characterized by comprising the following steps of: step one, reacting 4- (O- (2, 4, 6-triisopropyl) benzenesulfonyl) -uridine with N-tert-butyloxycarbonyl hydrazine to obtain a compound shown as a structural formula II,
Figure 588528DEST_PATH_IMAGE001
structural formula two, wherein R1, R2 are the same or different hydrocarbyl groups, R3 can be a carboxylate or a phosphate group;
step two, dissolving the compound shown in the structural formula two in a formic acid aqueous solution, stirring for 8-12h at room temperature, concentrating reaction liquid after the reaction is finished, and performing column chromatography separation to obtain the compound shown in the structural formula one,
Figure 505668DEST_PATH_IMAGE002
structural formula one, wherein R can be a carboxylate or a phosphate group.
2. The synthesis method of the pyrimidotriazole is characterized by comprising the following steps of: step one, reacting 4- (O- (2, 4, 6-triisopropyl) benzenesulfonyl) -uridine with hydrazine hydrochloride to obtain a compound shown as a structural formula III,
Figure 596990DEST_PATH_IMAGE003
structural formula III, wherein R1, R2 are the same or different hydrocarbyl groups, R3 can be a carboxylate or a phosphate group;
step two, dissolving the compound shown in the structural formula III in a formic acid aqueous solution, stirring for 8-12h at room temperature, concentrating reaction liquid after the reaction is finished, and performing column chromatography separation to obtain the compound shown in the structural formula I,
Figure 992199DEST_PATH_IMAGE004
structural formula one, wherein R can be a carboxylate or a phosphate group.
3. The method for synthesizing pyrimidotriazole according to claim 1 or 2, wherein the method comprises the following steps: the method comprises the following specific steps: the reaction temperature in the first step is room temperature, and the reaction solvent is acetonitrile or other solvents with the same solubility.
4. A pyrimidotriazole of the structural formula I or a pharmaceutically acceptable salt thereof:
Figure 806571DEST_PATH_IMAGE005
the structural formula I is shown in the specification,
wherein R may be a carboxylate or phosphate group.
5. A pharmaceutically acceptable salt of an N- (N-t-butoxycarbonylimino) cytosine nucleoside of the structural formula:
Figure 629034DEST_PATH_IMAGE006
the structural formula II is shown in the specification,
wherein R1, R2 are the same or different hydrocarbyl groups, and R3 can be a carboxylate or a phosphate group.
6. An N-aminocytosine nucleoside of structural formula iii a pharmaceutically acceptable salt thereof:
Figure 958384DEST_PATH_IMAGE007
the structural formula III is shown as the third,
wherein R1, R2 are the same or different hydrocarbyl groups, and R3 can be a carboxylate or a phosphate group.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112979733A (en) * 2021-04-25 2021-06-18 南京颐媛生物医学研究院有限公司 Anti-hepatitis B virus compound and preparation method and application thereof
CN113461760A (en) * 2021-09-06 2021-10-01 南京颐媛生物医学研究院有限公司 4-thiodeoxythymidine derivative and anti-hepatitis B virus pharmaceutical application thereof
CN113501853A (en) * 2021-09-13 2021-10-15 南京颐媛生物医学研究院有限公司 4-thiouracil deoxynucleoside phosphate and its antiviral medicine use

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112979733A (en) * 2021-04-25 2021-06-18 南京颐媛生物医学研究院有限公司 Anti-hepatitis B virus compound and preparation method and application thereof
CN112979733B (en) * 2021-04-25 2021-09-10 南京颐媛生物医学研究院有限公司 Anti-hepatitis B virus compound and preparation method and application thereof
CN113461760A (en) * 2021-09-06 2021-10-01 南京颐媛生物医学研究院有限公司 4-thiodeoxythymidine derivative and anti-hepatitis B virus pharmaceutical application thereof
CN113461760B (en) * 2021-09-06 2021-12-10 南京颐媛生物医学研究院有限公司 4-thiodeoxythymidine derivative and anti-hepatitis B virus pharmaceutical application thereof
CN113501853A (en) * 2021-09-13 2021-10-15 南京颐媛生物医学研究院有限公司 4-thiouracil deoxynucleoside phosphate and its antiviral medicine use

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