JP5227965B2 - Nitrotriazole derivative and method for producing compound using the same - Google Patents

Description

Cross-reference of related applications

  This application claims the priority of Japanese Patent Application No. 2007-260255 filed on Oct. 3, 2007 and Japanese Patent Application No. 2007-338931 filed on Dec. 28, 2007, the entire description of which is here Specifically incorporated by reference.

The present invention relates to a novel nitrotriazole derivative having 3-nitro-1H-1,2,4-triazole as a basic skeleton.
Furthermore, the present invention relates to a method for producing a compound useful as a reagent for introducing a protective group, synthesizing a pharmaceutical, or the like, using the nitrotriazole derivative.

Background Art Carbamate, carbonate, and thiocarbonate are compounds that are frequently used for the introduction of protecting groups in synthetic chemistry, and are also useful as synthetic intermediates for pharmaceuticals. There is much demand. At present, Alkyl Chloroformate type reagents and Succinimidyl / Benzotriazol-1-yl Carbamate type reagents are mainly used for these synthesis (for example, Wuts, PGM; Greene, TW "Greene's PROTECTIVE GROUPS in ORGANIC SYNTHESIS 4 ^th Ed. "WILEY-INTERSCIENCE, New Jersey, 2007., the entire description of which is hereby incorporated by reference.)

However, Alkyl Chloroformate type reagents have many liquids with unique unpleasant odors, and have low thermal stability and are difficult to handle. Furthermore, since there are many things which cannot be stored for a long time, it is necessary to prepare immediately before use. Further, since a base is essential for the reaction, it cannot be reacted with a compound having a substituent that is unstable under basic conditions. In addition, it takes a long time to complete the reaction, and further, there is a problem that the process becomes complicated over a long period of time because purification by extraction and column chromatography is essential. The Succinimidyl / Benzotriazol-1-yl Carbamate reagent also requires a long purification time and a purification process.
As other reagents, those having an azide as a leaving group are known, but due to the characteristics of the compound, handling is required with increasing scale.

DISCLOSURE OF THE INVENTION Accordingly, an object of the present invention is to provide a compound useful as a synthesis reagent for synthesizing carbamate, carbonate and thiocarbonate useful in synthetic chemistry by a simple process.

  As a result of intensive studies to achieve the above object, the present inventors have found a novel nitrotriazole derivative having 3-nitro-1H-1,2,4-triazole as a basic skeleton, and have completed the present invention. It came.

[一般式(I)中、Ｒは、置換基を有していてもよいアリールオキシ基もしくはヘテロアリールオキシ基、置換基を有するメトキシ基もしくはエトキシ基、置換基を有していてもよい炭素数３〜30のアルキルオキシ基、置換基を有するメチル基、置換基を有していてもよい炭素数２〜30のアルキル基、または置換基を有していてもよいアリール基もしくはヘテロアリール基を表す。]One embodiment of the present invention relates to a nitrotriazole derivative represented by the following general formula (I).

[In general formula (I), R represents an aryloxy group or heteroaryloxy group which may have a substituent, a methoxy group or an ethoxy group having a substituent, or a carbon number which may have a substituent. An alkyloxy group having 3 to 30; a methyl group having a substituent; an alkyl group having 2 to 30 carbon atoms which may have a substituent; or an aryl group or heteroaryl group which may have a substituent. Represent. ]

  In general formula (I), R can represent a methoxy group or ethoxy group having a substituent, or an alkyloxy group having 3 to 30 carbon atoms which may have a substituent.

[一般式(II)中、Ｘはアミノ基、アルキルもしくはアリールアミノ基、アルキルもしくはアリールオキシ基またはアルキルもしくはアリールチオ基を表す。]
で表される化合物と反応させることにより、下記一般式(III)：

[一般式(III)中、Ｒは一般式(I)における定義と同義であり、Ｘは一般式(II)における定義と同義である。]
で表される化合物を製造する方法に関する。In another embodiment of the present invention, the nitrotriazole derivative is represented by the following general formula (II):

[In the general formula (II), X represents an amino group, an alkyl or arylamino group, an alkyl or aryloxy group, or an alkyl or arylthio group. ]
Is reacted with a compound represented by the following general formula (III):

[In general formula (III), R has the same definition as in general formula (I), and X has the same definition as in general formula (II). ]
It relates to the method of manufacturing the compound represented by these.

  The reaction can be performed using dichloromethane and / or chloroform as a reaction solvent.

  The production method can include adding dichloromethane and / or chloroform to a reaction mixture of the nitrotriazole derivative and the compound represented by the general formula (II).

The nitrotriazole derivative of the present invention has high crystallinity, does not have deliquescence, and can be obtained as a stable and long-term storable crystal. In addition, since 3-nitro-1H-1,2,4-triazole, which is the basic skeleton, has low solubility in dichloromethane and chloroform, by using dichloromethane and / or chloroform as a reaction solvent, a secondary group as a leaving group can be obtained. While removing the generated 3-nitro-1H-1,2,4-triazole out of the reaction system, the reaction can proceed rapidly and quantitatively. In addition, in most cases, purification by column chromatography is not essential to obtain the target product, so there is an advantage that it is simple and environmentally friendly.
Furthermore, since the nitrotriazole derivative of the present invention can recover and reuse 3-nitro-1H-1,2,4-triazole by-produced in the synthesis of the above-mentioned target product, the aspect of resource reuse It is also an excellent reagent.

BEST MODE FOR CARRYING OUT THE INVENTION
[New nitrotriazole derivatives]
The novel nitrotriazole derivative of the present invention is represented by the following general formula (I).

In general formula (I), R is an aryloxy group or heteroaryloxy group which may have a substituent, a methoxy group or an ethoxy group having a substituent, or an optionally substituted carbon number 3 Represents an alkyloxy group having ˜30, a methyl group having a substituent, an alkyl group having 2 to 30 carbon atoms which may have a substituent, or an aryl group or heteroaryl group which may have a substituent; .
Hereinafter, the nitrotriazole derivative of the present invention will be described in more detail.

  In the general formula (I), when the group represented by R has a substituent, examples of the substituent include an alkyl group, a halogen atom, a nitro group, an amino group, a cyano group, a hydroxyl group, a carboxyl group, a carbamoyl group, An aryl group etc. can be mentioned. The alkyl group may be linear, branched or cyclic, and can be, for example, an alkyl group having 1 to 30 carbon atoms, specifically, methyl group, propyl group, isopropyl group, butyl group, isobutyl. Examples thereof include a group, s-butyl group, t-butyl group, pentyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, undecyl group, dodecyl group, and tridecyl group. The aryl group also includes a heteroaryl group, for example, a phenyl group, a naphthyl group, an anthranyl group, a biphenyl group, a 4-pyridyl group, a 2-pyridyl group, an imidazolyl group, a pyrrolyl group, an indolyl group, a furyl group. Can be mentioned.

  In the general formula (I), when R is an aryloxy group which may have a substituent, the aryl ring contained in the aryloxy group has, for example, 3 to 12 carbon atoms, preferably 6 to 8 carbon atoms. Yes, it may be monocyclic or polycyclic. The aryloxy group may have a substituent. Specific examples of the aryloxy group include substituted or unsubstituted phenoxy groups and naphthoxy groups, and more specific examples include the substituted aryloxy groups shown below. In the following, “•” represents a bonding position with carbonyl (C═O) in the general formula (I). Further, specific examples shown below include those useful as protecting groups. For these, the abbreviations as protecting groups are shown in parentheses. When the nitrotriazole derivative of the present invention contains a group useful as a protecting group, a compound represented by the general formula (III) useful as a protecting group introduction reagent is obtained by using it in the production method of the present invention described later. Can do.

  In the general formula (I), when R is a heteroaryloxy group which may have a substituent, the hetero atom contained therein includes a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S) And phosphorus atom (P). The heteroaryloxy group preferably has a substituent. Further, the heteroaryl ring contained in the heteroaryloxy group is preferably a 5- to 8-membered ring, and may be monocyclic or polycyclic. Specific examples of the heteroaryloxy group include a substituted or unsubstituted quinoloxy group, and more specifically include the following substituted heteroaryloxy groups.

  In general formula (I), R may be a methoxy group or ethoxy group having a substituent, or an alkyloxy group having 3 to 30 carbon atoms which may have a substituent. The alkyl moiety of the alkyloxy group may be linear, branched, cyclic, or a combination thereof, and has 3 to 30 carbon atoms, preferably 3 to 6 carbon atoms. If the carbon number is within the above range, the reactivity is good. The alkyloxy group preferably has a substituent. Specific examples of the substituted methoxy, substituted ethoxy group and substituted alkyloxy group are shown below.

  In general formula (I), R may be a methyl group having a substituent or an alkyl group having 2 to 30 carbon atoms which may have a substituent. If R is the above alkyl group, the reactivity is good. The alkyl group may be linear or branched or may have a cyclic structure. The carbon number is 2-30, preferably 2-6. The alkyl group preferably has a substituent. Specific examples of the aforementioned substituted methyl group and alkyl group are shown below.

In the general formula (I), when R is an aryl group which may have a substituent, the details of the aryl ring contained in the aryl group are as described above for the aryl ring contained in the aryloxy group. is there. When R is a heteroaryl group which may have a substituent, details of the heteroatom and the heteroaryl ring contained in the heteroaryl group are as described above for the heteroaryloxy group.
Specific examples of the aryl group and heteroaryl group are shown below.

  Specific examples of the group represented by R in the general formula (I) are shown above, but the present invention is not limited to these specific examples. From the viewpoint of the usefulness of the compound obtained by using the nitrotriazole derivative of the present invention, particularly as a reagent for introducing a protecting group, R has a methoxy or ethoxy group having a substituent, or a substituent. It is preferably an alkyloxy group having 3 to 30 carbon atoms.

  The nitrotriazole derivative of the present invention can be obtained by introducing a desired substituent R into nitrotriazole. Introduction of the substituent R into the nitrotriazole can be performed, for example, by reacting an acid halide having the desired substituent R with nitrotriazole according to the following scheme I. Some of the acid halides are commercially available, and can be synthesized by a known method. For example, acid chlorides can be easily synthesized by known methods shown in the following schemes II and III.

[上記において、Ｙはハロゲン原子（例えば塩素原子）を表し、Ｒは一般式(I)における定義と同義である。]

[In the above, Y represents a halogen atom (for example, chlorine atom), and R has the same definition as in formula (I). ]

  The above reaction can be performed in a suitable reaction solvent in the presence of a strong base such as sodium hydride, potassium hydride, or n-butyllithium. Moreover, the below-mentioned Example can also be referred about reaction conditions. Moreover, it can confirm that the target nitrotriazole derivative was obtained by well-known identification methods, such as NMR and elemental analysis. The nitrotriazole compound of the present invention may form a salt depending on the type of the substituent R, and may form a hydrate or a solvate in a free state or a salt state. The state is also included in the scope of the present invention. The nitrotriazole derivative of the present invention can be obtained as a crystal having high crystallinity and no deliquescence. Since the crystals thus obtained can be stored for a long time, they can be stored after synthesis until use.

[一般式(II)中、Ｘはアミノ基、アルキルもしくはアリールアミノ基、アルキルもしくはアリールオキシ基またはアルキルもしくはアリールチオ基を表す。]
で表される化合物と反応させることにより、下記一般式(III)：

[一般式(III)中、Ｒは一般式(I)における定義と同義であり、Ｘは一般式(II)における定義と同義である。]
で表される化合物を製造する方法に関する。[Method for producing compound]
The present invention relates to a nitrotriazole derivative represented by the general formula (I) represented by the following general formula (II):

[In the general formula (II), X represents an amino group, an alkyl or arylamino group, an alkyl or aryloxy group, or an alkyl or arylthio group. ]
Is reacted with a compound represented by the following general formula (III):

[In general formula (III), R has the same definition as in general formula (I), and X has the same definition as in general formula (II). ]
It relates to the method of manufacturing the compound represented by these.

  In the general formula (II), X represents an amino group, an alkyl or arylamino group, an alkyl or aryloxy group, or an alkyl or arylthio group. The alkylamino group represented by X may be a monoalkylamino group, a dialkylamino group, or an arylamino group. As monoalkylamino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, 1-phenylethylamino group, 2-phenylethylamino group, 1- A naphthylmethylamino group etc. can be mentioned. Examples of the dialkylamino group include those in which one alkyl group is substituted on the nitrogen atom of the monoalkylamino group. The substituted alkyl group may be linear, branched or cyclic, and can be, for example, an alkyl group having 1 to 30 carbon atoms, specifically a methyl group, a propyl group, an isopropyl group, butyl. Examples thereof include a group, isobutyl group, s-butyl group, t-butyl group, pentyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, undecyl group, dodecyl group, and tridecyl group. Examples of the arylamino group include those in which one aryl group is substituted on the nitrogen atom of the amino group. The substituted aryl group also includes a heteroaryl group, for example, a phenyl group, a naphthyl group, an anthranyl group, a biphenyl group, a 4-pyridyl group, a 2-pyridyl group, an imidazolyl group, a pyrrolyl group, an indolyl group, a furyl group. , Purine groups, pyrimidine groups, and the like.

  In the general formula (II), the details of the alkyl moiety of the alkyloxy group and alkylthio group represented by X are as described above for the alkyl group substituting the monoalkylamino group. Specific examples of the alkyloxy group represented by X may be linear, branched or cyclic, and may be, for example, an alkyloxy group having 1 to 30 carbon atoms, specifically a methoxy group. Propyloxy group, 2-propyloxy group, 1-butyloxy group, 2-butyloxy group, t-butyloxy group, pentyloxy group, cyclopropanoxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, un A decyloxy group, a dodecyloxy group, a tridecyloxy group, etc. can be mentioned. Specific examples of the aryloxy group represented by X include a heteroaryl group, for example, a phenyloxy group, a naphthyloxy group. , Anthranyloxy group, biphenyloxy group, 4-pyridyloxy group, 2-pyridyloxy group, benzotri A soloxy group, a furan-2-oxy group, and the like can be exemplified, and specific examples of the alkylthio group represented by X may be linear, branched, or cyclic. Specifically, a methylthio group, a propylthio group, a 2-propylthio group, a butylthio group, a 1-butylthio group, a s-butylthio group, a t-butylthio group, a pentylthio group, a cyclopropylthio group, A cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, an undecylthio group, a dodecylthio group, a tridecylthio group, and the like can be mentioned. Specific examples of the arylthio group represented by X include a heteroaryl group, for example, , Phenylthio group, p-phenylthio group, naphthylthio group, anthranylthio group, biphenylthio group Examples include o group and benzothiazole-2-thio group.

  The amino group, alkylamino group, arylamino group, alkyloxy group, aryloxy group, alkylthio group, and arylthio group described above can each have a substituent. Examples of the substituent include those exemplified as the substituent that R in the general formula (I) may have.

The compound represented by the general formula (II) can be synthesized by a known method, and some compounds are commercially available. For more information about known methods, Larock, RC In Comprehensive Organic Transformations : a guide to functional group preparations 2 nd Ed .; Wiley-VCH: reference may be made to 1999.. The entire description is hereby specifically incorporated by reference.

  In the method for producing a compound represented by the general formula (III) of the present invention, the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) are reacted in an appropriate reaction solvent. Thus, a compound represented by the general formula (III) can be obtained. As the reaction solvent, dichloromethane, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran (THF), water-dichloromethane mixed solvent, water-chloroform mixed solvent, water-ethyl acetate mixed solvent, water-tetrahydrofuran (THF) mixed solvent, etc. are used. be able to. Nitrotriazole is poorly soluble in dichloromethane and chloroform, so by using dichloromethane and / or chloroform as a reaction solvent, 3-nitro-1H-1,2,4-triazole is generated as a by-product as a leaving group. The reaction can proceed promptly and quantitatively while removing from the reaction system. Alternatively, by adding dichloromethane and / or chloroform to the reaction mixture, 3-nitro-1H-1,2,4-triazole, which is a by-product, is removed from the reaction system, and the reaction is performed quickly and quantitatively. It can also be advanced. In addition, 3-nitro-1H-1,2,4-triazole by-produced by the reaction can be easily recovered after the reaction. The recovered 3-nitro-1H-1,2,4-triazole can be reused for the synthesis of the compound represented by the general formula (I). This is preferable in terms of resource reuse, and is a great advantage of the present invention.

  Specific embodiments of the production method of the present invention include the following methods A to F. Method A is suitable when X in the general formula (II) is an amino group or an alkyl or arylamino group, that is, when the compound represented by the general formula (II) is an amine. Method B is suitable when the compound represented by the general formula (II) is an amine and the target product is to be obtained with higher purity, and the embodiment D is suitable when it is desired to obtain higher purity. Among them, since the method A does not require a base or an activating reagent, it is a simple method that can obtain the target product only by filtering out the nitrotriazole precipitated in the system. Methods C and E can be used when the compound represented by the general formula (II) is an amine (particularly an amine having a relatively weak nucleophilic power), and X in the general formula (II) is It can also be used when it is an alkyl or aryloxy group or an alkyl or arylthio group, that is, when the compound represented by the general formula (II) is an alcohol or a thiol. Method C is suitable when the compound represented by the general formula (II) is an amine or thiol, and Method E is suitable when the compound represented by the general formula (II) is an alcohol. In each method, the reaction can be performed at about 0 to 40 ° C., specifically at room temperature, and the reaction time can be about 5 minutes to 24 hours.

Method A
In the reaction solvent, the nitrotriazole derivative represented by the general formula (I) is stirred with the compound represented by the general formula (II), the precipitated nitrotriazole is filtered off, and the solvent is distilled off to remove the general formula. The target compound represented by (III) is obtained. Here, the mixing ratio of the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) is 1: 1 as a molar ratio. The amount of the reaction solvent can be about 0.1 to 1M in terms of the concentration of the nitrotriazole derivative represented by the general formula (I).

Method B
After stirring the nitrotriazole derivative represented by the general formula (I) with the compound represented by the general formula (II) in the reaction solvent, washing and drying, and distilling off the solvent, the general formula (III) The target compound represented is obtained. Here, dichloromethane and / or chloroform is used as a reaction solvent, and / or dichloromethane and a reaction mixture of a nitrotriazole derivative represented by the general formula (I) and a compound represented by the general formula (II) Addition of chloroform is preferable because the reaction can proceed rapidly and quantitatively while removing 3-nitro-1H-1,2,4-triazole as a by-product from the reaction system. Specifically, the nitrotriazole derivative represented by the general formula (I) is added to dichloromethane and / or chloroform, the compound represented by the general formula (II) is added and stirred, and further dichloromethane is added and saturated. After washing with an aqueous sodium hydrogen carbonate solution and drying over anhydrous sodium sulfate, the target product is obtained by distilling off the solvent. Alternatively, when using a reaction solvent other than dichloromethane and / or chloroform, add dichloromethane and / or chloroform to the reaction mixture, then wash with saturated aqueous sodium bicarbonate, dry over anhydrous sodium sulfate, and then evaporate the solvent. By doing so, the target object can be obtained. The mixing ratio and the addition amount of the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) are as described above for the method A.

Method C
In a reaction solvent, a nitrotriazole derivative represented by the general formula (I), a compound represented by the general formula (II) and a base are added and stirred. Next, after washing and drying, the target compound represented by the general formula (III) is obtained by distilling off the solvent. Specifically, a nitrotriazole derivative represented by the general formula (I) is added to dichloromethane and / or chloroform, and a compound represented by the general formula (II) and a base (for example, triethylamine, 2,6-lutidine, etc.) ) And stirred, further dichloromethane is added, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the desired product. The mixing ratio and the addition amount of the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) are as described above for the embodiment A. Moreover, the usage-amount of a base can be about 1-10 equivalent, for example.

Method D
In Method B, the solvent is distilled off, and the residue is separated and purified by column chromatography to obtain the target compound. However, the mixing ratio of the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) is a molar ratio, for example, about 1: 1 to 5: 1.

Method E
In Method C, the solvent is distilled off, and the residue is separated and purified by column chromatography to obtain the target compound. However, the mixing ratio of the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) is a molar ratio, for example, about 1: 1 to 5: 1.

Method F
In a reaction solvent, a nitrotriazole derivative represented by the general formula (I), a compound represented by the general formula (II) and a base are added and stirred. Next, after washing and drying, the target compound represented by the general formula (III) is obtained by distilling off the solvent. Specifically, the nitrotriazole derivative represented by the general formula (I) was added to a mixed solvent of 5% NaHCO ₃ aqueous solution and dichloromethane, the compound represented by the general formula (II) was added and stirred, and further dichloromethane was added. After washing with a saturated aqueous solution of sodium bicarbonate and drying over anhydrous sodium sulfate, the solvent is distilled off to obtain the desired product. The mixing ratio and the addition amount of the nitrotriazole derivative represented by the general formula (I) and the compound represented by the general formula (II) are as described above for the method A.

  By the production method of the present invention, carbamates, carbonates and thiocarbonates useful as synthetic intermediates for protecting group introduction reagents, pharmaceuticals and the like in synthetic chemistry can be obtained. According to the production method of the present invention, a target substance can be obtained without using a base or an activating reagent. In this case, the target substance can be obtained only by filtering out 3-nitro-1H-1,2,4-triazole precipitated in the system. When dichloromethane is used as the reaction solvent, 3-nitro-1H-1,2,4-triazole slightly dissolved in dichloromethane can be completely removed by washing as necessary.

  Furthermore, the methods A to C are simple and environmentally friendly methods because the target substance can be obtained without performing purification by column chromatography. Furthermore, as described above, by using dichloromethane as a reaction solvent, 3-nitro-1H-1,2,4-triazole can be recovered and reused, so that it can be used in the reuse of resources. It is an excellent method.

Examples Hereinafter, the present invention will be further described by way of examples. However, this invention is not limited to the aspect shown in the Example. In the following, “NT” refers to 3-nitro-1H-1,2,4-triazole.

[Synthesis Example 1]
Synthesis of Benzyl 3-nitro-1H-1,2,4-triazole-1-carboxylate

According to the above synthesis scheme, Benzyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (hereinafter referred to as “Z-NT”) was synthesized by the following method.
NaH (60 mass% in paraffin liquid) 411.2 mg was azeotropically dried with hexane (10 ml × 3) in an Ar atmosphere and then dried under reduced pressure to obtain NaH 249.6 mg (10.4 mmol). On the other hand, a THF solution (30 ml) of NT 1.19 g (10.4 mmol) azeotropically dried with pyridine (5 ml × 3) and toluene (5 ml × 3) was added under Ar atmosphere, and 10 minutes at 0 ° C. Stir. While the solution was stirred at 0 ° C, 1.48 ml (10.4 mmol) of Z-Cl was added, stirred at 0 ° C for 30 minutes, and then stirred at room temperature for 12 hours. The salt was filtered off and the solvent was distilled off, followed by recrystallization from EtOAc to obtain the target compound (yield 95%, needle-like crystals, light yellow). The identification results are shown below.
mp: 112-113 ° C (dec.); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.99 (1H, s), 7.55-7.42 (5H, m), 5.54 (2H, s); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 163.1, 147.1, 146.0, 132.4, 129.9, 129.4, 129.0, 72.5; Anal.calcd for for C ₁₀ H ₈ N ₄ O ₄・ 1 / 4H ₂ O: C, 47.53; H, 3.39; N, 22.17. Found: C, 47.37; H, 3.32; N, 22.04.

[Synthesis Example 2]
The synthesis of 2,2,2-Trichloroethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate was carried out in the same manner as in Synthesis Example 1 except that the starting material was changed. Trichloroethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate (hereinafter referred to as “Troc-NT”) was synthesized (yield 92%, prismatic crystals, light yellow). A synthesis scheme and identification results are shown below.

mp: 145-146 ° C (dec.); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (1H, s), 5.17 (2H, s); ¹³ C NMR (125 MHz, CD ₃ CN) δ 164.2, 149.6, 146.1, 94.0, 78.0; Anal.calcd for C ₅ H ₃ Cl ₃ N ₄ O ₄ : C, 20.75; H, 1.04; N, 19.36.Found: C, 20.08; H, 1.07; N, 19.65.

[Synthesis Example 3]
Synthesis of 9H-Fluorenylmethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate 9H-Fluorenylmethyl 3-nitro-1H-1 by the same method as in Synthesis Example 1 except that the starting material was changed. , 2,4-triazole-1-carboxylate (hereinafter referred to as “Fmoc-NT”) was synthesized (yield 95%, needle-like crystals, light yellow). A synthesis scheme and identification results are shown below.

mp: 170-171 ° C (dec.); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (1H, s), 7.80 (2H, d, J = 7.3 Hz), 7.64 (2H, d, J = 7.3 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.35 (2H, t, J = 7.3 Hz), 4.86 (2H, d, J = 7.1 Hz), 4.45 (1H, t, J = 7.1 Hz) ; ¹³ C NMR (125 MHz, CD ₃ COCD ₃ ) δ 164.1, 149.1, 147.1, 143.7, 142.1, 129.0, 128.2, 126.2, 121.0, 72.4, 47.1; Anal.calcd for C ₁₇ H ₁₂ N ₄ O ₄ : C , 60.71; H, 3.60; N, 16.66. Found: C, 60.57; H, 3.69; N, 16.87.

[Synthesis Example 4]
Synthesis of 2- (Trimethylsilyl) ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate 2- (trimethylsilyl) ethyl 3 in the same manner as in Synthesis Example 1, except that the starting material was changed. -nitro-1H-1,2,4-triazole-1-carboxylate (hereinafter referred to as “Teoc-NT”) was synthesized (yield 96%, needle-like crystals, light yellow). A synthesis scheme and identification results are shown below.

mp: 85-86 ° C (dec.); ¹ H NMR (500 MHz, CD ₃ CN) δ 8.97 (1H, s), 4.67-4.60 (2H, m), 1.27-1.20 (2H, m), 0.08 ( 9H, s); ¹³ C NMR (125 MHz, CD ₃ CN) δ164.0, 148.8, 147.2, 70.8, 17.9, -1.7.

[Synthesis Example 5]
Synthesis of Anisoyl 3-nitro-1H-1,2,4-triazole

According to the above synthesis scheme, Anisoyl 3-nitro-1H-1,2,4-triazole (hereinafter referred to as “Ani-NT”) was synthesized by the following method.
NaH (60 mass% in paraffin liquid) 398.3 mg was azeotropically dried with hexane (10 ml × 3) in an Ar atmosphere and then dried under reduced pressure to obtain NaH 202.0 mg (8.4 mmol). To this, under an Ar atmosphere, a THF solution (20 ml) of NT 958 mg (8.4 mmol) azeotropically dried with pyridine (5 ml × 3) and toluene (5 ml × 3) was added, and at 0 ° C. for 10 minutes. Stir. While stirring the solution at 0 ° C., 1.14 ml (8.4 mmol) of Anisoyl chloride was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 12 hours. The salt was filtered off and the solvent was distilled off, followed by recrystallization from EtOAc to obtain the desired compound (yield 92%, needle-like crystals, light yellow). The identification results are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (1H, s), 8.36 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 3.95 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 162.5, 161.4, 146.7, 134.7, 119.3, 114.3, 55.7.

[Synthesis Example 6]
Synthesis of t-Butoxy 3-nitro-1H-1,2,4-triazole-1-carboxylate t-butoxy 3-nitro-1H-1 was carried out in the same manner as in Synthesis Example 5 except that the starting material was changed. , 2,4-triazole-1-carboxylate (hereinafter referred to as “Boc-NT”) was synthesized (yield 55%, light yellow). A synthesis scheme and identification results are shown below.

mp: 77-78 ° C (dec.); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (1H, s), 1.71 (9H, s); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 162.9, 146.6, 144.0, 90.5, 27.7.

[Synthesis Example 7]
Synthesis of Phenoxyacetyl 3-nitro-1H-1,2,4-triazole Phenoxyacetyl 3-nitro-1H-1,2,4-triazole (hereinafter referred to as “Phenoxyacetyl 3-nitro-1H-1,2,4-triazole”) , “Pac-NT”) (yield 65%, plate-like crystals, light yellow). A synthesis scheme and identification results are shown below.

¹ H NMR (400 MHz, CD ₃ CN) δ 9.10 (1H, s), 7.37-7.29 (2H, m), 7.08-6.98 (3H, m), 5.49 (2H, s); ¹³ C NMR (100 MHz , CD ₃ CN) δ 166.3, 163.4, 157.9, 146.7, 130.3, 122.7, 115.4, 66.7.

[Synthesis Example 8]
Synthesis of Phenoxycarbonyl 3-nitro-1H-1,2,4-triazole Phenoxycarbonyl 3-nitro-1H-1,2,4-triazole (hereinafter referred to as “Phenoxycarbonyl 3-nitro-1H-1,2,4-triazole”) , “Px-NT”) (yield 87%, crystals, light yellow). A synthesis scheme and identification results are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.06 (1H, s), 7.56-7.49 (2H, m), 7.44-7.39 (1H, m), 7.37-7.32 (2H, m); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.2, 149.3, 147.3, 144.6, 130.0, 127.7, 120.3.

[Synthesis Example 9]
Palmitoyl 3-nitro-1H-1,2,4 -triazole synthesis starting materials except for changing the, in the same manner as in Synthesis Example 5, Palmitoyl 3-nitro-1H -1,2,4-triazole ( hereinafter , “Pal-NT”) (yield 95%, needle-like crystals, light yellow). A synthesis scheme and identification results are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.94 (1H, s), 3.18 (2H, t, J = 7.4 Hz), 1.82 (2H, quintet, J = 7.4 Hz), 1.47-1.22 (24H, m) , 0.88 (3H, t, J = 6.8 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.6, 162.5, 144.4, 34.3, 32.0, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 29.2, 28.9, 23.6, 22.8, 14.3.

  The nitrotriazole derivatives obtained in Synthesis Examples 1 to 9 all had high crystallinity, no deliquescence, and high stability.

[Example 1]
Synthesis of Benzyl (R) -1-phenylethylcarbamate (2) (Method A)

  Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 2) (quantitative, white solid).

The identification results of the compound synthesized in Example 1 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.23 (10H, m), 5.13 (1H, d, J = 12.2 Hz), 5.04 (1H, d, J = 12.2 Hz), 5.09 (1H, br) , 4.93-4.81 (1H, m), 1.49 (3H, d, J = 6.8 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.1, 143.1, 136.1, 128.3, 128.2, 127.8, 127.0, 125.6, 66.5 , 50.6, 22.4; MS (MALDI TOF) m / z calcd for C ₁₆ H ₁₇ NNaO ₂ [M + Na] ⁺ 278.12, found 277.99.

[Example 2]
Synthesis of 2,2,2-Trichloroethyl (R) -1-phenylethylcarbamate (3)

(1) Synthesis by Method A Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 3) (quantitative (containing 4% NT), white solid).

(2) Synthesis by Method B Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 3) (yield 88%, white solid).

The identification results of the compound synthesized in Example 2 are shown below.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46-7.20 (5H, m), 5.28 (1H, brs), 4.88 (1H, dq, J = 7.0, 7.0 Hz), 4.75 (1H, d, J = 11.7 Hz), 4.67 (1H, d, J = 11.7 Hz), 1.53 (3H, d, J = 7.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.5, 142.6, 128.6, 127.4, 125.8, 95.5, 74.5, 51.1, 22.4; MS ( FAB) m / z calcd for C 11 H 13 C l3 NO 2 [M + H] + 296.00, found 296.06.

[Example 3]
Synthesis of (9H-Fluoren-9-yl) methyl (R) -1-phenylethylcarbamate (4)

(1) Synthesis by Method A Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 4) (quantitative (including NT), white solid).

(2) Synthesis by Method B Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (compound 4) (yield 96%, white solid).

The identification results of the compound synthesized in Example 3 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (2H, d, J = 7.3 Hz), 7.57 (2H, d, J = 7.3 Hz), 7.48-7.12 (9H, m), 5.04 (1H, brs) , 4.85 (1H, brs), 4.40 (2H, brd, J = 6.8 Hz), 4.18 (1H, brs), 1.47 (3H, brd, J = 5.6 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.3, 143.7, 141.1, 128.5, 127.5, 127.2, 126.9, 125.8, 124.9, 124.8, 119.8, 66.5, 50.7, 47.4, 22.5; MS (MALDI TOF) m / z calcd for C ₂₃ H ₂₁ NNaO ₂ (M + Na ] ⁺ 366.15, found 366.12.

[Example 4]
2- (Trimethylsilyl) ethyl (R) -1-phenylethylcarbamate (5) (Method F)

Teoc-NT (100 μmol) obtained in Synthesis Example 4 was added to a 5% aqueous NaHCO ₃ solution and dichloromethane (1 ml), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the target product (compound 5) was obtained by distilling off the solvent (yield 95%, colorless oil).

The identification results of the compound synthesized in Example 4 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.22 (5H, m), 4.91 (1H, brs), 4.91-4.76 (1H, m), 4.20-4.08 (2H, m), 1.47 (3H, d , J = 6.8 Hz), 0.96 (2H, t, J = 8.5 Hz), 0.02 (9H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.7, 143.5, 128.4, 127.1, 125.8, 63.0, 50.5 , 22.6, 17.9, -1.3; MS (MALDI TOF) m / z calcd for C ₁₄ H ₂₃ NNaO ₂ Si [M + Na] ⁺ 288.14, found 288.18.

[Example 5]
Benzyl 2,6-dimethylmorpholine-4-carboxylate (7)

(1) Synthesis by Method A Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 7) (quantitative (containing 2% NT), white solid).

(2) Synthesis by Method B Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 7) (yield 89%, white solid).

The identification results of the compound synthesized in Example 5 are shown below.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48-7.24 (5H, m), 5.14 (2H, s), 3.98 (2H, brs), 3.55 (2H, brs), 2.55 (2H, brs), 1.17 ( 6H, d, J = 5.9 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.8, 136.4, 128.4, 127.9, 127.8, 71.6, 67.2, 49.2, 18.8; MS (MALDI TOF) m / z calcd for C ₁₄ H ₁₉ NNaO ₃ [M + Na] ⁺ 272.13, found 271.99.

[Example 6]
Synthesis of 2,2,2-Trichloroethyl 2,6-dimethylmorpholine-4-carboxylate (8)

(1) Synthesis by Method A Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 8) (quantitative (including NT), white solid).

(2) Synthesis by Method B Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 8) (yield 92%, white solid).

The identification results of the compound synthesized in Example 6 are shown below.
¹ H NMR (300 MHz, CDCl ₃ ) δ 4.78 (1H, s), 4.76 (1H, s), 3.99 (2H, brd, J = 13.2 Hz), 3.60 (2H, m), 2.67 (1H, t, J = 12.1 Hz), 2.58 (1H, t, J = 12.1 Hz), 1.20 (3H, d, J = 6.2 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.0, 95.5, 75.0, 71.7, 71.7 , 49.6, 49.4, 18.8; MS (FAB) m / z calcd for C ₉ H ₁₅ Cl ₃ NO ₃ [M + H] ⁺ 290.01, found 290.07.

[Example 7]
Synthesis of (9H-Fluoren-9-yl) methyl 2,6-dimethylmorpholine-4-carboxylate (9)

(1) Synthesis by Method A Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 9) (quantitative (including NT), colorless oil).

(2) Synthesis by Method B Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (compound 9) (quantitative, colorless oil).

The identification results of the compound synthesized in Example 7 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (2H, d, J = 7.3 Hz), 7.55 (2H, d, J = 7.3 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.31 (2H , t, J = 7.3 Hz), 4.64-4.32 (2H, m), 4.24 (1H, t, J = 6.5 Hz), 3.95 (1H, brs), 3.71 (1H, brs), 3.47 (1H, brs) , 3.37 (1H, brs), 2.50 (2H, brs), 1.14 (6H, brs); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.7, 143.8, 141.2, 127.5, 126.9, 124.7, 119.8, 71.6, 67.2 , 49.5, 49.1, 47.5, 18.7; MS (MALDI TOF) m / z calcd for C ₂₁ H ₂₃ NNaO ₃ [M + Na] ⁺ 360.16, found 360.14.

[Example 8]
Synthesis of 2- (Trimethylsilyl) ethyl 2,6-dimethylmorpholine-4-carboxylate (10) (Method A)

  Teoc-NT (100 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), then compound 6 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 10) (quantitative, colorless oil).

The identification results of the compound synthesized in Example 8 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 4.22-4.12 (2H, m), 4.08-3.80 (2H, m), 3.58-3.48 (2H, m), 2.54-2.42 (2H, m), 1.17 (6H , d, J = 6.1 Hz), 1.04-1.96 (2H, m), 0.04 (9H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.2, 71.7, 63.7, 49.1, 18.8, 17.9, -1.3 ; MS (FAB) m / z calcd for C ₁₂ H ₂₅ NNaO ₃ Si [M + Na] ⁺ 282.15, found 282.22.

[Example 9]
Synthesis of Benzyl (1S, 2R) -2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (12) (Method A)

  Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then Compound 11 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 12) (yield 95%, white solid).

The identification results of the compound synthesized in Example 9 are shown below.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44-7.12 (9H, m), 5.56-5.36 (1H, m), 5.20-5.04 (3H, m), 4.55 (1H, bs), 3.10 (1H, dd , J = 16.5, 4.8 Hz), 2.88 (1H, dd, J = 16.5, 1.7 Hz), 2.29 (1H, br); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.6, 140.3, 139.5, 136.1, 128.4 , 128.1, 128.0, 128.0, 127.0, 125.2, 124.3, 73.5, 67.1, 59.3, 39.5; MS (MALDI TOF) m / z calcd for C ₁₇ H ₁₇ NNaO ₃ [M + Na] ⁺ 306.11, found 306.02.

[Example 10]
Synthesis of 2,2,2-Trichloroethyl (1S, 2R) -2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (13)

(1) Synthesis by Method A Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then Compound 11 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 13) (yield 95% (including 4% NT), white solid).

(2) Synthesis by Method B Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then compound 11 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 13) (yield 92%, white solid).

The identification result of the compound synthesize | combined in Example 10 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.21 (4H, m), 5.73 (1H, brd, J = 8.3 Hz), 5.14 (1H, dd, J = 8.3, 5.0 Hz), 4.86 (1H, d, J = 12.0 Hz), 4.74 (1H, d, J = 12.0 Hz), 4.62 (1H, dt, J = 5.0, 2.0 Hz), 3.16 (1H, dd, J = 16.6, 5.0 Hz), 2.93 ( 1H, dd, J = 16.6, 2.0 Hz), 2.09 (1H, brs); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.8, 139.9, 139.4, 128.3, 127.2, 125.3, 124.4, 95.5, 74.7, 73.5, 59.4, 39.7; MS (MALDI TOF) m / z calcd for C ₁₂ H ₁₂ Cl ₃ NNaO ₃ [M + Na] ⁺ 345.98, found 345.94.

[Example 11]
Synthesis of (9H-Fluoren-9-yl) methyl (1S, 2R) -2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (14)

(1) Synthesis by Method A Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then Compound 11 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 14) (quantitative (including NT), white solid).

(2) Synthesis by Method B Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then Compound 11 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 14) (yield 94%, white solid).

The identification result of the compound synthesize | combined in Example 11 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (2H, d, J = 7.5 Hz), 7.62 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.5 Hz), 7.31 (2H , t, J = 7.3 Hz), 7.22 (4H, brs), 5.39 (1H, brs), 5.12 (1H, brs), 4.62-4.48 (3H, m), 4.25 (1H, t, J = 6.6 Hz) , 3.12 (1H, dd, J = 16.4, 4.6 Hz), 2.90 (1H, d, J = 16.4 Hz), 1.97 (1H, brs); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.6, 143.7, 141.2 , 141.2, 140.2, 139.5, 128.1, 127.6, 127.1, 126.9, 126.9, 125.2, 124.9, 124.3, 119.9, 73.5, 66.8, 59.3, 47.4, 39.6; MS (MALDI TOF) m / z calcd for C ₂₄ H ₂₁ NNaO ₃ [M + Na] ⁺ 394.14, found 394.16.

[Example 12]
Synthesis of 2- (Trimethylsilyl) ethyl (1S, 2R) -2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (15) (Method F)

Teoc-NT (100 μmol) obtained in Synthesis Example 4 was added to a 5% aqueous NaHCO ₃ solution and dichloromethane mixture (1 ml), then compound 11 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the target object (compound 15) was obtained by distilling a solvent off (quantitative, yellow solid).

The identification result of the compound synthesize | combined in Example 12 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31-7.20 (5H, m), 5.34 (1H, brs), 5.17-5.05 (1H, m), 4.63-4.54 (1H, m), 4.23 (2H, t , J = 8.5 Hz), 3.12 (1H, dd, J = 16.6, 5.2 Hz), 2.91 (1H, dd, J = 16.6, 1.9 Hz), 2.40 (1H, br), 1.02 (2H, t, J = 8.5 Hz), 0.06 (9H, s); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 157.2, 140.6, 139.8, 128.2, 127.1, 125.3, 124.4, 73.5, 63.5, 59.1, 39.4, 17.7, -1.5; MS (MALDI TOF) m / z calcd for C ₁₅ H ₂₃ NNaO ₃ Si [M + Na] ⁺ 316.13, found 316.06.

[Example 13]
Synthesis of Benzyl 4-phenylpiperazine-1-carboxylate (17)

(1) Synthesis by Method A Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then compound 16 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 17) (quantitative (containing 10% NT), yellow oil).

(2) Synthesis by Method B Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then Compound 16 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 17) (yield 91%, yellow oil).

The identification result of the compound synthesize | combined in Example 13 is shown below.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44-7.18 (6H, m), 6.96-6.84 (3H, m), 5.16 (2H, s), 3.66 (4H, t, J = 5.0 Hz), 3.14 ( 4H, brs); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.0, 151.0, 136.4, 129.0, 128.4, 127.9, 127.8, 120.3, 116.6, 67.2, 49.5, 43.8; MS (MALDI TOF) m / z calcd for C ₁₈ H ₂₀ N ₂ NaO ₂ [M + Na] ⁺ 319.14, found 319.08.

[Example 14]
Synthesis of 2,2,2-Trichloroethyl 4-phenylpiperazine-1-carboxylate (18) (Method A)

  Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then compound 16 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 18) (quantitative, light yellow oil).

The identification results of the compound synthesized in Example 14 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31-7.25 (2H, m), 6.96-6.87 (3H, m), 4.78 (2H, s), 3.72 (4H, brd, J = 18.8 Hz), 3.22- 3.15 (4H, m); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.2, 150.8, 129.1, 120.5, 116.7, 95.6, 75.1, 49.5, 44.1; MS (MALDI TOF) m / z calcd for C ₁₃ H ₁₆ Cl ₃ N ₂ O ₂ [M + H] ⁺ 337.03, found 336.98.

[Example 15]
Synthesis of (9H-Fluoren-9-yl) methyl 4-phenylpiperazine-1-carboxylate (19)

(1) Synthesis by Method A Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then Compound 16 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 19) (quantitative (including NT), pale yellow oil).

(2) Synthesis by Method B Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then compound 16 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 19) (yield 93%, pale yellow oil).

The identification results of the compound synthesized in Example 15 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (2H, d, J = 7.6 Hz), 7.60 (2H, d, J = 7.1 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.33 (2H , t, J = 7.1 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 8.3 Hz), 6.93 (1H, d, J = 8.3 Hz), 6.92 (2H, t , J = 8.3 Hz), 4.49 (2H, d, J = 6.6 Hz), 4.27 (1H, t, J = 6.6 Hz), 3.62 (4H, brs), 3.12 (4H, brs); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.9, 150.9, 143.7, 141.1, 129.0, 127.5, 126.9, 124.8, 120.3, 119.8, 116.6, 67.3, 49.4, 47.4, 43.8; MS (MALDI TOF) m / z calcd for C ₂₅ H ₂₅ N ₂ O ₂ [M + H] ⁺ 385.19, found 385.19.

[Example 16]
Synthesis of 2- (Trimethylsilyl) ethyl 4-phenylpiperazine-1-carboxylate (20) (Method A)

  Teoc-NT (100 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), then compound 16 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 20) (quantitative, yellow solid).

The identification results of the compound synthesized in Example 16 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (2H, dd, J = 7.6, 7.3 Hz), 6.93 (2H, d, J = 7.6 Hz), 6.89 (1H, t, J = 7.3 Hz), 4.22 (2H, t, J = 8.4 Hz), 3.63 (4H, t, J = 4.9 Hz), 3.14 (4H, t, J = 4.9 Hz), 1.03 (2H, t, J = 8.4 Hz), 0.05 (9H , s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.4, 151.0, 129.0, 120.2, 116.6, 63.7, 49.5, 43.7, 17.9, -1.3; MS (MALDI TOF) m / z calcd for C ₁₆ H ₂₇ N ₂ O ₂ Si [M + H] ⁺ 307.18, found 307.08.

[Example 17]
Synthesis of Benzyl 3-hydroxypropylcarbamate (22)

(1) Synthesis by Method A Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then Compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 22) (quantitative (including NT), colorless oil).

(2) Synthesis by Method B Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), then compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Next, the solvent was distilled off to obtain the desired product (Compound 22) (yield 94%, colorless oil).

(3) Synthesis by Method C Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), triethylamine (200 μmol) and compound 21 (100 μmol) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 22) (yield 97%, colorless oil).

The identification result of the compound synthesize | combined in Example 17 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.28 (5H, m), 5.12 (1H, brs), 5.11 (2H, s), 3.67 (2H, t, J = 5.8 Hz), 2.64 (1H, br), 3.35 (2H, q, J = 5.8 Hz), 1.70 (2H, quintet, J = 5.8 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 157.2, 136.3, 128.4, 128.0, 128.0, 66.9, 59.5, 37.8, 32.6; MS (MALDI TOF) m / z calcd for C ₁₁ H ₁₅ NNaO ₃ [M + Na] ⁺ 232.09, found 231.90.

[Example 18]
Synthesis of 2,2,2-Trichloroethyl 3-hydroxypropylcarbamate (23)

(1) Synthesis by Method A Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then Compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 23) (quantitative (containing 2% NT), colorless oil).

(2) Synthesis by Method B Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 23) (yield 95%, colorless oil).

The identification results of the compound synthesized in Example 18 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.41 (1H, brs), 4.74 (2H, s), 3.73 (2H, t, J = 6.0 Hz), 3.41 (2H, q, J = 6.0 Hz), 2.41 (1H, brs), 1.76 (2H, quintet, J = 6.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ155.0, 95.3, 74.4, 59.7, 38.1, 32.2; MS (MALDI TOF) m / z calcd for C ₆ H ₁₁ Cl ₃ NO ₃ [M + H] ⁺ 249.98, found 249.81.

[Example 19]
Synthesis of (9H-Fluoren-9-yl) methyl 3-hydroxypropylcarbamate (24)

(1) Synthesis by Method A Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 24) (quantitative (including NT), white solid).

(2) Synthesis by Method B Fmoc-NT (100 μmol) obtained in Synthesis Example 3 was added to dichloromethane (500 μl), then compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 24) (yield 93%, white solid).

The identification results of the compound synthesized in Example 19 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (2H, d, J = 7.6 Hz), 7.57 (2H, d, J = 7.6 Hz), 7.39 (2H, t, J = 7.6 Hz), 7.30 (2H , t, J = 7.6 Hz), 5.06 (1H, brs), 4.42 (2H, d, J = 6.6 Hz), 4.20 (1H, t, J = 6.6 Hz), 3.72-3.52 (2H, m), 3.40 -3.28 (2H, m), 2.60 (1H, brs), 1.80-1.58 (2H, m); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 157.1, 143.7, 141.1, 127.5, 126.9, 124.8, 119.8, 66.6 , 59.5, 47.3, 37.7, 32.6; MS (MALDI TOF) m / z calcd for C ₁₈ H ₁₉ NNaO ₃ [M + Na] ⁺ 320.13, found 320.06.

[Example 20]
Synthesis of 2- (Trimethylsilyl) ethyl 3-hydroxypropylcarbamate (25) (Method A)

  Teoc-NT (100 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), then compound 21 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (Compound 25) (quantitative, colorless oil).

The identification result of the compound synthesize | combined in Example 20 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 4.99 (1H, brs), 4.17 (2H, t, J = 8.4 Hz), 3.69 (2H, t, J = 5.9 Hz), 3.34 (2H, q, J = 5.9 Hz), 1.71 (2H, quintet, J = 5.9 Hz), 0.99 (2H, t, J = 8.4 Hz), 0.04 (9H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 157.6, 63.3, 59.4, 37.5, 32.8, 17.9, -1.3; MS (MALDI TOF) m / z calcd for C ₉ H ₂₁ NNaO ₃ Si [M + Na] ⁺ 242.12, found 242.10.

[Example 21]
Synthesis of Benzyl phenylcarbamate (27) (Method E)

  Z-NT (200 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), triethylamine (500 μmol) and compound 26 (100 μmol) were added, and the mixture was stirred at room temperature for 15 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was separated and purified by column chromatography (Hexane: EtOAc = 9: 1) to obtain the desired product (Compound 27) (yield 87%, white solid).

The identification result of the compound synthesize | combined in Example 21 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.25 (9H, m), 7.05 (1H, t, J = 7.3 Hz), 6.72 (1H, brs), 5.18 (2H, s); ¹³ C NMR ( 100 MHz, CDCl ₃ ) δ 153.1, 137.6, 135.9, 128.9, 128.5, 128.2, 128.1, 123.4, 118.6, 67.0; MS (MALDI TOF) m / z calcd for C ₁₄ H ₁₃ NNaO ₂ [M + Na] ⁺ 250.08 , found 249.91.

[Example 22]
Synthesis of 2,2,2-Trichloroethyl phenylcarbamate (28)

(1) Synthesis by Method A Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then Compound 26 (100 μmol) was added, and the mixture was stirred at room temperature for 15 minutes. The precipitated nitrotriazole was filtered off and the solvent was distilled off to obtain the desired product (compound 28) (quantitative (containing 4% Troc-NT), white solid).

(2) Synthesis by Method B Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then Compound 26 (100 μmol) was added, and the mixture was stirred at room temperature for 15 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 28) (yield 97%, white solid).

The identification results of the compound synthesized in Example 22 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (4H, m), 7.14-7.08 (1H, m), 6.95 (1H, brs), 4.82 (2H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 151.3, 136.8, 129.0, 124.0, 118.8, 95.2, 74.5; MS (FAB) m / z calcd for C ₉ H ₈ Cl ₃ NNaO ₂ [M + Na] ⁺ 289.95, found 290.00.

[Example 23]
Synthesis of 2- (Trimethylsilyl) ethyl phenylcarbamate (29) (Method E)

  Teoc-NT (200 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), triethylamine (500 μmol) and compound 26 (100 μmol) were added, and the mixture was stirred at room temperature for 60 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was separated and purified by column chromatography (Hexane: EtOAc = 9: 1) to obtain the desired product (Compound 29) (yield 94%, yellow oil).

The identification results of the compound synthesized in Example 23 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.24 (4H, m), 7.05 (1H, t, J = 7.3 Hz), 6.59 (1H, brs), 4.29-4.23 (2H, m), 1.08- 1.02 (2H, m), 0.06 (9H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.5, 137.8, 128.8, 123.1, 118.5, 63.5, 17.9, -1.3; MS (FAB) m / z calcd for C ₁₂ H ₁₉ NNaO ₂ Si [M + Na] ⁺ 260.11, found 260.16.

[Example 24]
Synthesis of 2,2,2-Trichloroethyl 4- (phenylthio) phenylcarbamate (31) (Method D)

  Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), then compound 30 (100 μmol) was added, and the mixture was stirred overnight at room temperature. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was separated and purified by column chromatography (Hexane: EtOAc = 9: 1) to obtain the desired product (Compound 31) (yield 92%, orange solid).

The identification results of the compound synthesized in Example 24 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.34 (4H, m), 7.30-7.17 (5H, m), 6.93 (1H, brs), 4.82 (2H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 151.2, 136.5, 136.4, 133.0, 130.0, 129.0, 126.5, 119.5, 95.1, 74.5.

[Example 25]
Synthesis of Dibenzyl carbonate (33) (Method C)

  Z-NT (100 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), triethylamine (200 μmol) and compound 32 (100 μmol) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 33) (yield 98%, colorless oil).

The identification results of the compound synthesized in Example 25 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.24 (10H, m), 5.16 (4H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.7, 134.8, 128.2, 128.2, 128.0, 69.5; MS (FAB) m / z calcd for C ₁₅ H ₁₄ NaO ₃ [M + Na] ⁺ 265.08, found 265.13.

[Example 26]
Synthesis of Benzyl 2,2,2-trichloroethyl carbonate (34) (Method C)

  Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), triethylamine (200 μmol) and compound 32 (100 μmol) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain the desired product (Compound 34) (yield 96%, colorless oil).

The identification results of the compound synthesized in Example 26 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.32 (5H, m), 5.24 (2H, s), 4.77 (2H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.7, 134.3, 128.7 , 128.5, 128.3, 94.3, 76.8, 70.7; MS (FAB) m / z calcd for C ₁₀ H ₉ Cl ₃ NaO ₃ [M + Na] ⁺ 304.95, found 305.02.

[Example 27]
Synthesis of Benzyl 2- (trimethylsilyl) ethyl carbonate (35) (Method C)

  Troc-NT (100 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), triethylamine (200 μmol) and compound 32 (100 μmol) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 35) (yield 92%, colorless oil).

The identification results of the compound synthesized in Example 27 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.30 (5H, m), 5.15 (2H, s), 4.27-4.21 (2H, m), 1.09-1.03 (2H, m), 0.04 (9H, s ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.1, 135.4, 128.5, 128.3, 128.2, 69.3, 66.6, 17.6, -1.5; MS (FAB) m / z calcd for C ₁₃ H ₂₀ NaO ₃ Si [M + Na] ⁺ 275.11, found 275.17.

[Example 28]
Synthesis of Benzyl (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl carbonate (37) (Method E)

  Z-NT (200 μmol) obtained in Synthesis Example 1 was added to dichloromethane (500 μl), triethylamine (500 μmol) and compound 36 (100 μmol) were added, and the mixture was added at room temperature and stirred for 1 hour. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was separated and purified by column chromatography (Hexane: EtOAc = 9: 1) to obtain the desired product (Compound 37) (yield 95%, white solid).

The identification results of the compound synthesized in Example 28 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.28 (5H.m), 5.15 (1H, s), 5.14 (1H, s), 4.53 (1H, dt, J = 10.0, 4.4 Hz), 2.11- 2.05 (1H, m), 1.95 (1H, doublet of quintet, J = 7.0, 2.7 Hz), 1.71-1.64 (2H, m), 1.54-1.40 (1H, m), 1.40 (1H, tt, J = 12.0 , 3.2 Hz), 1.05 (2H, q, J = 11.8 Hz), 0.91 (3H, d, J = 6.6 Hz), 0.88 (3H, d, J = 6.6 Hz), 0.88-0.81 (1H, m), 0.78 (3H, d, J = 7.1 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.7, 135.3, 128.4, 128.2, 128.0, 78.6, 69.3, 47.1, 40.8, 34.2, 31.5, 26.1, 23.4, 22.1 , 20.9, 16.4; MS (FAB) m / z calcd for C ₁₈ H ₂₆ NaO ₃ [M + Na] ⁺ 313.18, found 313.18.

[Example 29]
Synthesis of 2,2,2-Trichloroethyl (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl carbonate (38) (Method E)

  Troc-NT (200 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), triethylamine (500 μmol) and compound 36 (100 μmol) were added, and the mixture was added at room temperature and stirred for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was separated and purified by column chromatography (Hexane: EtOAc = 9: 1) to obtain the desired product (Compound 38) (yield 96%, white solid).

The identification results of the compound synthesized in Example 29 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 4.79 (1H, d, J = 11.9 Hz), 4.76 (1H, d, J = 11.9 Hz), 4.60 (1H, dt, J = 11.0, 4.5 Hz), 2.12 -2.05 (1H, m), 1.98 (doublet of quintet, J = 6.9, 2.7 Hz), 1.75-1.65 (2H, m), 1.55-1.43 (2H, m), 1.12 (1H, q, J = 11.8 Hz ), 1.12-1.00 (1H, m), 0.93 (3H, d, J = 6.4 Hz), 0.91 (3H, d, J = 7.1 Hz), 0.91-0.85 (1H, m), 0.80 (3H, d, J = 7.1 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.6, 94.7, 80.0, 76.5, 47.0, 40.6, 34.1, 31.6, 26.3, 23.5, 22.1, 20.8, 16.4; MS (MALDI TOF) m / z calcd for C ₁₃ H ₂₂ Cl ₃ O ₃ [M + H] ⁺ 331.06, found 331.16.

[Example 30]
Synthesis of 2- (Trimethylsilyl) ethyl (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl carbonate (39) (Method E)

  Teoc-NT (200 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), triethylamine (500 μmol) and compound 36 (100 μmol) were added, and the mixture was added at room temperature and stirred for 1 hour. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was separated and purified by column chromatography (Hexane: EtOAc = 9: 1) to obtain the desired product (Compound 39) (yield 97%, white solid).

The identification result of the compound synthesize | combined in Example 30 is shown below.
¹ H NMR (500 MHz, CDCl ₃ ) δ 4.50 (1H, dt, J = 11.0, 4.6 Hz), 4.25-4.16 (2H, m), 2.10-2.04 (1H, m), 1.97 (doublet of quintet, J = 6.9, 2.8 Hz), 1.71-1.64 (2H, m), 1.54-1.43 (1H, m), 1.40 (1H, tt, J = 11.5, 3.2 Hz), 1.10-1.00 (4H, m), 0.91 ( 3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6.8 Hz), 0.91-0.83 (1H, m), 0.79 (3H, d, J = 6.9 Hz), 0.05 (9H, s); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 155.0, 78.0, 66.0, 47.0, 40.8, 34.1, 31.4, 26.0, 23.3, 22.0, 20.7, 17.5, 16.2, -1.6; MS (FAB) m / z calcd for C ₁₆ H ₃₂ NaO ₃ Si [M + Na] ⁺ 323.20, found 323.21.

[Example 31]
Synthesis of O-2,2,2-Trichloroethyl S-4-methoxyphenyl carbonothioate (41) (Method C)

  Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), triethylamine (200 μmol) and compound 40 (100 μmol) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 41) (quantitative, colorless oil).

The identification result of the compound synthesize | combined in Example 31 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (2H, d, J = 9.8 Hz), 6.93 (2H, d, J = 9.8 Hz), 4.81 (2H, s), 3.83 (2H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.7, 160.9, 136.6, 114.9, 94.3, 75.7, 55.5; MS (FAB) m / z calcd for C ₁₀ H ₉ Cl ₃ NaO ₃ S [M + Na] ⁺ 336.92, found 336.95.

[Example 32]
Synthesis of O-2,2,2-Trichloroethyl S-propyl carbonothioate (43) (Method C)

  Troc-NT (100 μmol) obtained in Synthesis Example 2 was added to dichloromethane (500 μl), triethylamine (200 μmol) and compound 42 (100 μmol) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 43) (yield 94%, colorless oil).

The identification results of the compound synthesized in Example 32 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 4.83 (2H, s), 2.91 (2H, t, J = 7.3 Hz), 1.71 (2H, tq, J = 7.3, 7.3 Hz), 1.01 (3H, t, J = 7.3 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.5, 94.5, 75.4, 33.3, 23.1, 13.3.

[Example 33]
Synthesis of 2 ', 3', 5'-O-Tris-t-butyldimethylsilyl-4-N- [2- (trimethylsilyl) ethoxycarbonyl] -cytidine (44) (Method D)

Teoc-NT (100 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), compound 44 (50 μmol) was added, and the mixture was stirred at room temperature for 1 hour. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off, and the residue was separated and purified by column chromatography (MeOH: CH ₂ Cl ₂ = 98: 2) to obtain the desired product (compound 45) (quantitative, colorless oil).

The identification results of the compound synthesized in Example 33 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (1H, d, J = 7.3 Hz), 7.58 (1H, brs), 7.17 (1H, d, J = 7.3 Hz), 5.79 (1H, brs), 4.32 -4.25 (2H, m), 4.17-4.08 (3H, m), 4.07-4.02 (1H, m), 3.80 (1H, d, J = 11.2 Hz), 1.10-1.03 (2H, m), 0.97 (9H , s), 0.92 (9H, s), 0.89 (9H, s), 0.24 (3H, s), 0.16 (3H, s), 0.14 (3H, s), 0.13 (3H, s), 0.06 (9H, s), 0.05 (6H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.0, 154.8, 152.3, 144.5, 93.9, 90.8, 83.0, 76.2, 68.9, 64.8, 60.7, 26.2, 26.0, 26.0, 18.7 , 18.2, 17.6, -1.3, -3.9, -4.0, -4.9, -5.0, -5.0, -5.4; MS (MALDI TOF) m / z calcd for C ₃₃ H ₆₇ N ₃ NaO ₇ Si ₄ [M + Na ] ⁺ 752.40, found 752.60.

[Example 34]
Synthesis of 2 ', 3', 5'-O-Tris-t-butyldimethylsilyl-6-N- [2- (trimethylsilyl) ethoxycarbonyl] -adenosine (47) (Method D)

Teoc-NT (200 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), compound 46 (50 μmol) was added, and the mixture was stirred at room temperature for 12 hours. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off, and the residue was separated and purified by column chromatography (MeOH: CH ₂ Cl ₂ = 99: 1) to obtain the desired product (Compound 47) (yield 98%, colorless oil).

The identification results of the compound synthesized in Example 34 are shown below.
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.74 (1H, s), 8.32 (1H, s), 8.25 (1H, brs), 6.08 (1H, d, J = 5.2 Hz), 4.67 (1H, dd, J = 5.2, 4.5 Hz), 4.43-4.28 (3H, m), 4.19-4.12 (1H, m), 4.03 (1H, dd, J = 11.4, 3.9 Hz), 3.80 (1H, dd, J = 11.4, 2.8 Hz), 1.17-1.05 (2H, m), 0.96 (9H, s), 0.94 (9H, s), 0.79 (9H, s), 0.15 (3H, s), 0.14 (3H, s), 0.11 ( 6H, s), 0.07 (9H, s), -0.04 (3H, s), -0.26 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.6, 150.9, 150.8, 149.2, 141.4, 122.1 , 88.3, 85.6, 75.9, 72.0, 64.5, 62.5, 26.2, 26.0, 25.8, 18.7, 18.2, 18.0, 17.8, -1.3, -4.2, -4.5, -4.5, -4.9, -5.2, -5.2; MS ( MALDI TOF) m / z calcd for C ₃₄ H ₆₇ N ₅ NaO ₆ Si ₄ [M + Na] ⁺ 776.41, found 776.60.

[Example 35]
Synthesis of 2 ', 3', 5'-O-Tris-t-butyldimethylsilyl-2-N- [2- (trimethylsilyl) ethoxycarbonyl] -guanosine (49) (Method E)

Teoc-NT (200 μmol) obtained in Synthesis Example 4 was added to dichloromethane (500 μl), triethylamine (500 μmol) and compound 48 (50 μmol) were added, and the mixture was stirred at room temperature for 4 hours. After adding 4 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off, and the residue was separated and purified by column chromatography (MeOH: CH ₂ Cl ₂ = 99: 1) to obtain the desired product (Compound 49) (yield 80%, colorless oil).

The identification result of the compound synthesize | combined in Example 35 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 11.30 (1H, brs), 8.04 (1H, s), 7.47 (1H, brs), 5.86 (1H, d, J = 5.4 Hz), 4.38-4.32 (3H, m), 4.26 (1H, dd, J = 4.4, 3.4 Hz), 4.09 (1H, ddd, J = 3.4, 3.2, 2.2 Hz), 3.92 (1H, dd, J = 11.5, 3.2 Hz), 3.78 (1H , dd, J = 11.5, 2.2 Hz), 1.12-1.05 (2H, m), 0.96 (9H, s), 0.94 (9H, s), 0.81 (9H, s), 0.14 (3H, s), 0.13 ( 3H, s), 0.11 (3H, s), 0.10 (3H, s), 0.08 (9H, s), -0.02 (3H, s), -0.21 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.3, 153.1, 148.2, 146.2, 136.8, 120.7, 87.3, 85.6, 76.9, 72.1, 66.0, 62.7, 26.2, 25.9, 25.7, 18.6, 18.2, 18.0, 17.7, -1.4, -4.2, -4.4, -4.5, -4.9, -5.2, -5.3. HRMS (FAB ⁺ ) m / z calcd for C ₃₄ H ₆₇ N ₅ NaO ₇ Si ₄ [M + Na] ⁺ 792.4015, found 792.4020.

[Example 36]
Synthesis of Benzyl (R) -1-phenylethylcarbamate (2) (Method B)

  Z-NT (100 μmol) obtained in Synthesis Example 1 was added to THF (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 15 minutes. After adding 3 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous solution of sodium bicarbonate (3 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 2) (yield 94%, white solid).

[Example 37]
Synthesis of Benzyl (R) -1-phenylethylcarbamate (2) (Method B)

Z-NT (100 μmol) obtained in Synthesis Example 1 was added to CH ₃ CN (500 μl), then Compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 15 minutes. After adding 3 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous solution of sodium bicarbonate (3 ml × 3) and dried over anhydrous sodium sulfate. Next, the solvent was distilled off to obtain the desired product (Compound 2) (yield 96%, white solid).

[Example 38]
Synthesis of t-Butyl (R) -1-phenylethylcarbamate (50) (Method B)

Boc-NT (100 μmol) was added to THF (500 μl), then compound 1 (100 μmol) was added, and the mixture was stirred at room temperature for 60 minutes. After adding 3 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous solution of sodium bicarbonate (3 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 50) (quantitative, white solid).

The identification results of the compound synthesized in Example 38 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.16 (5H, m), 4.80 (2H, brs), 1.64-1.20 (12H, brs).

[Example 39]
Synthesis of t-Butyl 4-phenylpiperazine-1-carboxylate (52) (Method B)

  Boc-NT (100 μmol) was added to dichloromethane (500 μl), then compound 51 (100 μmol) was added, and the mixture was stirred at room temperature for 15 minutes. After further adding 3 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (3 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off to obtain the desired product (Compound 52) (quantitative, white solid).

The identification results of the compound synthesized in Example 39 are shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31-7.23 (2H, m), 6.96-6.85 (3H, m), 3.58 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 1.48 (9H, s).

[Example 40]
Synthesis of N, N'-Bispalmitoyl-L-lysine ethyl ester (54) (Method F)

Pal-NT (200 μmol) was added to a 5% aqueous NaHCO ₃ solution and dichloromethane mixture (1 ml), then compound 53 (100 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. After adding 5 ml of dichloromethane to the reaction mixture, it was washed with a saturated aqueous sodium hydrogen carbonate solution (5 ml × 3) and dried over anhydrous sodium sulfate. Subsequently, the target product (Compound 54) was obtained by distilling off the solvent (yield 93%, white solid).

The identification result of the compound synthesize | combined in Example 40 is shown below.
¹ H NMR (400 MHz, CDCl ₃ ) δ 6.20 (1H, d, J = 7.8 Hz), 5.76-5.70 (1H, m), 4.56 (1H, dt, J = 8.1, 4.4 Hz), 4.19 (2H, q, J = 7.2 Hz), 3.27-3.20 (2H, m), 2.23 (2H, t, J = 7.6 Hz), 2.16 (2H, t, J = 7.7 Hz), 1.89-1.78 (1H, m), 1.73-1.48 (7H, m), 1.40-1.19 (53H, m), 0.88 (6H, t, J = 6.8 Hz); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 173.2, 173.0, 172.4, 61.5, 51.7 , 38.9, 36.9, 36.7, 32.3, 32.0, 29.8, 29.8, 29.6, 29.5, 29.5, 29.5, 29.4, 28.9, 26.0, 25.8, 22.8, 22.5, 14.3, 14.3.

  According to the present invention, various carbamates, carbonates and thiocarbonates useful in synthetic chemistry can be obtained simply and efficiently.

Claims (5)

A nitrotriazole derivative represented by the following general formula (I).

[In general formula (I), R represents an aryloxy group or heteroaryloxy group which may have a substituent, a methoxy group or an ethoxy group having a substituent, or a carbon number which may have a substituent. An alkyloxy group having 3 to 30; a methyl group having a substituent; an alkyl group having 2 to 30 carbon atoms which may have a substituent; or an aryl group or heteroaryl group optionally having a substituent. Represent. ] The nitrotriazole derivative according to claim 1, wherein R in the general formula (I) represents a methoxy group or an ethoxy group having a substituent, or an alkyloxy group having 3 to 30 carbon atoms which may have a substituent. . The nitrotriazole derivative according to claim 1 or 2 is represented by the following general formula (II):

[In the general formula (II), X represents an amino group, an alkyl or arylamino group, an alkyl or aryloxy group, or an alkyl or arylthio group. ]
Is reacted with a compound represented by the following general formula (III):

[In general formula (III), R has the same definition as in general formula (I), and X has the same definition as in general formula (II). ]
The method to manufacture the compound represented by these. The said reaction is a manufacturing method of Claim 3 performed using a dichloromethane and / or chloroform as a reaction solvent. The production according to claim 3 or 4, comprising adding dichloromethane and / or chloroform to a reaction mixture of the nitrotriazole derivative according to claim 1 or 2 and the compound represented by the general formula (II). Method.