JPH0276861A - Novel fluorine-containing 3-nitro-1,2,4-triazole and radiosensitizer containing same compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is fluorine-containing organic group). EXAMPLE:3-(3'-Nitro-1'-triazol)-2,2-difluoropropionic acid methyl ester. USE:A radiosensitizer. PREPARATION:The compound of formula I can be produced by the addition reaction of a fluorine-containing epoxy compound to the compound of formula II. The reaction is carried out at 0-100 deg.C, preferably 50-70 deg.C without using a solvent or in an alcohol, dioxane, etc.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to 3-nitro-1.2 having a fluorine-containing substituent.
．． The present invention relates to a 4-triazole compound and a radiosensitizer containing the same as an active ingredient. More specifically, a fluorine-containing radiosensitizer containing a specific fluorine-containing nitrotriazole compound as an active ingredient, which promotes the inactivation of refractory and hypoxic cells present in malignant tumors by radiation irradiation. Regarding drugs.

[Background Art] Methods for suppressing the proliferation of malignant tumor cells include radiation irradiation, administration of antitumor compounds, and administration of immune substances, and these methods are actually used in the treatment of malignant tumors, either in conjunction with surgical therapy or alone. There is. Among these, radiation irradiation is one method that has been used for many years.

Hypoxia cell sensitizers (or radiosensitizers), which are drugs that increase the sensitivity of hypoxic cells to radiation, are being developed as a powerful means to improve the therapeutic effect of radiation.

In the past, many attempts have been made to develop hypoxic cell sensitizers (for example, "Cancer and Chemotherapy", Vol. 8, No. 11 (1932)).
See page 1659 (November 2006). ).

Misonidazole, one of the representative compounds of hypoxic cell sensitizers, has been shown to be approximately twice as effective as no additive in animal transplantation tumor experiments; Therefore, it is difficult to administer an effective dose, and no sensitizing effect was observed when applied to humans (see reference 4 cited in "Cancer and Chemotherapy" above).
.

In order to increase radiation sensitizing activity and reduce neurotoxicity, we are proceeding with the investigation of new nitrotriazole derivatives in place of nitroimidazole (for example,
(See Japanese Unexamined Patent Publication No. 194019/1983). However, the sensitizing effect is still insufficient.

By the way, previous research has revealed that the radiosensitizing function of azole compounds originates from the azole ring, and that the side chain portion is involved in the lipophilicity and expression of pharmacological properties of the compound. International Journal of Radiation Biology (Int.
J, Radiat, Biol, ) (1979) V
ol, 35. 151).

On the other hand, compounds in which a fluorine atom is introduced at a specific position in the compound are being used in pharmaceuticals because of the fluorine atom's mimetic effect, metabolic inhibition effect, and changes in fat solubility (for example, Area of Chemistry: Volume 35, 441
(See page (+981)).

[Objective and Structure of the Invention] Therefore, the present inventors aimed to find a compound having a high radiosensitizing effect among nitrotriazole derivatives.
We synthesized various compounds in which some or all of the side chains were replaced with fluorine atoms, and tested their radiosensitizing effects.

As a result, the formula: %Formula% 1 In the formula, R represents a fluorine-containing organic group. Indicated by 3-
The dil.rho1.2.4-triazole derivative significantly increases the sensitivity of hypoxic cells to radiation, and in addition, animal studies have shown that the pharmacokinetics are significantly improved compared to conventional compounds, with low toxicity and low neurogenicity. It was discovered that it can be a new toxic radiosensitizer. Therefore, the gist of the present invention is as shown by the above formula (+),
The present invention relates to a 3-nitro-12,4-triazole derivative having a fluorine-containing substituent and a radiosensitizer containing the same as an active ingredient.

In the present invention, R is a formula: %Formula%([[) In the formula, , or X and )' represent =0. Z is a hydrogen atom, a fluorine atom, CI to C which may be substituted with a hydroxyl group, an alkyl group is a fluorine-containing alkyl group, the formula: -(CHE)-C0-0RI (where R is a hydrogen atom , C, -C5 alkyl group is a fluorine-containing alkyl group, E is a hydrogen atom, f2 is a fluorine atom, and the following is 0 or 1.) Formula: -Co-R.

(Here, R7 is C1 to C, and is a fluorine-containing alkyl group like an alkyl group.) / Formula: -(CHE)x-Go-N \ (Here, R1 and R4 are the same or different and are a hydrogen atom, Hydroxyl group or hydroxyl group, C1-C
, a C, -CS alkyl group or a fluorine-containing alkyl group which may be substituted with an alkokene group or an amide group, or Ro and R4 together with the nitrogen atom form a 3- to 6-membered ring.

E and π have the same seven color meanings as above. ) / Expression・-(CHE)! N \ (R3, R4, E, π: Same meaning as Doe) R1 / Formula: -(CHE)zN \ R4 1: (R3, R4, ESη: Same meaning as above) R3 / Formula: -(C)IE)tN \ C.R.

(R,, R4, R17 have the same meanings as above) Formula Knee (C1 (
E) τAR6 (Here, A is an oxygen atom or a sulfur atom, R5 is a hydrogen atom, M is a hydroxyl group, and C is optionally substituted with a 01-C5 okyniane group, which seems to be a C1-C5 alkoxyl group)
I-C, an alkyl group or a fluorine-containing alkyl group, or 10 o 1e (Re is C1-C, an alkyl group, or:
YoR? CHCHt I A \ / / \ Rs Rm (Here, R7 is a Cl-07 alkylene group, R8 is 01-
C, alkyl group, A has the same meaning as above. ). E and scraps: Same meaning as above. ) or f2 represents an atom or group represented by the formula: -(CHE) OCRs (R5 is 01 to C, an alkyl group or a fluorine-containing alkyl, E and x have the same meanings as above). Furthermore, with Y and Z = CF
-CF3 or = CHORs (R
e is a 01-C6 fluorine-containing alkyl group). i represents an integer from θ to 2. The derivative (1) which is a fluorine-containing secondary group represented by - is preferred. Particularly preferred are derivatives <n in which the group R is bonded to the nitrogen atom of the triazole ring and the secondary elementary atom or r2 has at least one fluorine atom on the carbon atom bonded to the carbon atom.

In formula (1), preferred examples of the substituent R are as follows: (1) CHt CF t COCH31H (2) CHt CF t CN CHt CHt
OCH3(3) CHv CF t CN CHt
CHt OH(4) CHCHt CN H(CH
t ) t OCH3 units CFa O (5) CHCHt COCHz CF2 0 CH (6) CHt CHCHt OCHt CF t
CF t H(7) CH, CHF-CH, OC
H31: (8) aHtcHFcHzOccHs chant (9) CHtCHF -CH,0H (10)
CH, CH=CH0CHtCF3(11) -CF
=CF -CF3 (12) -CFtCFtH CH (13) CHtcH-cHtr (14) CHyCHFCNH(CHy)tOH(1
5) CHzCF 3 (16) CHaCF tc OCR3 (17)
CHzCOCF 3 (1g) CHt COCHF t (19) CH2C0CHtF (22) CHtCFCN(CtHs)tF3 CH3 (23) eH,cH/ \F 3 CF3 j / (25) CHtCFtCHtOI-1 (27)
CtltCFtCHtSCtls (2g)
CPyCN(CHz)tOHO (30) -CF CN H(CHJ20
HP30 (31) -CI[CHFCNH(CI(t)tOH
ll.

Ct■3 0 (33) -CHFt (34) -CONH(CH2)3CF3(35)
-CH, Cl-1, CHI"2 (36) -C
I-(, F (37) -CI-LCHFCOCHzz: (33) -CHtCIIFCNHCHtCHtOC
! (*(39) CHtCFtCHtNH2(4
0) CHzCFyC)-rtkiHCCH3(4
1) -C) [2CP2CH2N ICCH
,CH,○ HI3 :1 (43) -CH,CF,CNH2 (44) -CH,CF,CNHO)[(45)
-CII? CF,CNHCHtCH,'<H3CQ.

(4B) CHtCFtCHz:':HCl
-1tC1-(tOcl-h(47) -CH,
Cl-1)'CS t[CI-1, CH, OH (4g
) O CHt CF t CS HCHt CH3 (49
) O CHt CF t CN HCHt CHt CH3C
Ht CF t CN H(CH!) s CH3-
CHt CF t CSHCHt CF 5i -CHt CF , C! "ζ H (CHri3CF
3-cH, cr, c, \l-I CH(CH*)t) Knee CI-(, Cr', C>ζHC(CH3)5(56)
O Ct-1t CV t CNH(CHt)tOcHtc
Hs-CtrcFtcNH(CHt)30CHtC
H*CH, CFzCNI■(CF(t)30cH3-C
H, CF, CNl-1 (CH,) 301-1 (60)
O0H-CHtCFtCN
I(CHffi Cf(CH3)1 -CHtCFtcNH(CHJtO(CHt)yo)[
(62) OO-CH2CF2CNHCH2CH,CNH.

CH2Cl-I P CI (20C[42CH, O
CI-13-CH2CHr;' C1,1,OC82C
1-ICI(2\/ /\ 83CCH3 -CH,CHFCHloCH,CHCH!OHOH CHtOCHCHs CH,0H -CH,CHF CH,OCH,CHlOI-1 The compound of the present invention can be synthesized, for example, as follows. .

(A) In the formula, when R is a fluorine-containing alkyl group, a fluorine-containing epoxy compound is subjected to an addition reaction. (The result is a fluorine-containing alkyl group having an OH group.) The reaction temperature is 0 to 100°C, preferably 50 to 70°C, and a reaction solvent is not particularly necessary, but alcohols, dioxane, etc. can be used. can.

(2) The OH group of the compound obtained in (1) was replaced with a fluorinating agent [
For example, diethylaminosulfur trifluoride (D
AST)).

The reaction conditions include an aprotic solvent such as methylene chloride,
The reaction temperature is 0-50°C in chloroform, °ether.

is subjected to an addition reaction with a fluorine-containing olefin.

The second reaction is carried out in the presence of a base in an aprotic solvent (e.g.
acetonitrile, dimethylformamide), temperature θ~
Perform at 100°C.

In formula (B), when R is a fluorine-containing ester group, a fluorine-containing α,β-unsaturated carbonyl compound is subjected to an addition reaction.

This reaction is carried out in the presence of an acid or base in an aprotic solvent (e.g. dioxane, tetrahydrofuran) at a temperature of 30 to
Perform at 120°C.

Then, a fluorine-containing oxetane is reacted.

This reaction is carried out in an alcoholic solvent (eg methyl alcohol, ethyl alcohol) at a temperature of 0 to 50°C.

When R in the formula (C) is a fluorine-containing amide, the compound (B) is further reacted with an amine compound.

This reaction does not particularly require a solvent. The reaction temperature is 0
-100°C.

(D) In formula 2, when R is a fluorine-containing amine (1) (C)
The compound is reduced with a suitable reducing agent. The reducing agent may be one that does not reduce the nitro group, for example, B t
Ha etc. should be used. Any solvent can be used as long as it does not deactivate the reducing agent, such as tetrahydrofuran, dioxane, etc.

(E) In the case where R is a fluorine-containing amide, the compound of (1) (D) is reacted with a carboxylic acid halide, carboxylic acid anhydride, lactone, etc. Although a solvent is not particularly necessary, when a carboxylic acid halide is used, pyridine, morpholine, etc. may be used as a base catalyst.

Among the above synthetic methods, typical reactions are shown in the following formulas.

(A) (1) 8111-SH NT Te CH, CHCH, F H (A) (2) CH, CHCH, F --→ CHtCHFCH, F
□ H (A) (3) (H) (1) (B) (2) ;1 (C) (1) NT -11--> CH, CHF CNR3R'i (D) ( 1) CI'1-CFtCNHR' NT ■ C112CF2CHtNHR' (E) (1) NT 1 -” R'C0XCH
tCF tC) [tN H2 CHt CF v CH! N HCR' (wherein, R1
, Rt represents H or a lower alkyl group. X represents halogen. Compound (1) of the present invention is useful as a sensitizer in radiotherapy, and the dosage varies depending on the type of tumor and the compound, but in general, the oral dosage is 20 to 10
000 places, 0.5 to +ooooR9 for injections, and 20 to 10,000 degrees 9 for suppositories. The optimal dose is based on the doctor's judgment according to the symptoms, and depends on the type of radiation, irradiation dose,
It is determined by the irradiation division degree, etc.

There are no particular restrictions on the dosage form of the compound (1) of the present invention, and those commonly used in the pharmaceutical field can be used as carriers, and +At
! J is done.

Examples of the production of the compound (r) of the present invention and its radiation sensitizing effect are shown below using specific examples.

Production example 1 3-nitro-1,2,4-triazole 1.509 (1
3.2 mmol) and sodium carbonate 3.0O9 (28゜3 mmol), methanol 30af7 was added, and while stirring at room temperature, tetrafluorooxecone 2゜O9 (28゜3 mmol) was added.
9 (21 mmol) was added dropwise. After stirring the reaction solution for 30 minutes at room temperature, it is concentrated, and the concentrate is separated between ethyl acetate and water. After drying the ethyl acetate layer with magnesium sulfate, filtration,
The filtrate was concentrated, and the 1-condensate was isolated and purified by silica gel column chromatography to give 1.529% of methyl 3-(3'-nitro-beetriazole)-2,2-difluoropropionate.
I got it. m, p.

60.8~62,5℃'HN~IR (CDCfh); δ=3.98 (3H,
s.

-OCH3), 4.97 (2H,t, -NCHt, Jt
(F=131(z), 8.40 (I H,s, I(
s).

19F i) I N R (T F , A standard), 30.
8ppm.

Production Example 2 3-(3'-nitro-l°-triazole)-2°2-
Methyl difluoropropionate 7702iF (3-26
2-methoxyethylamine (0.4 x 12 mmol) was dissolved in 5 m of dioxane (II:
ol)e was added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, the concentrate was isolated and purified using silica gel column chromatography to obtain 3-(3'-nitro-1'-triazole)-2
,2-difluoropropionic acid methoxyethylamide 5
Obtained 70m9. m, p, 66-68°C.

'HNMR(CDC(3); δ=3.34(3H,s
.

-CH5), 3.3 0 to 3.5 8 (4H, m
, -CH.

CH*0-), 5.00(2H,t,
H8, JHF=13Hz), 6.91 (I H, b
s, -CONH-), 8.38 (I H, s, Hs).

“F MN R (CD Cρ3XTFA standard), 31.
3Pffla Production Example 3 3-(3°-nitro=l°-triazole)-2°2-
Methyl difluoropropionate 520i9 (2゜'l
Q mmol) was dissolved in dioxane 4J112, and ethanolamine 190 m9c3, 1 mmol was dissolved in dioxane 4J112.
) and treated in the same manner as in Production Example 2 to produce 3-(3'-nitro-1).

-triazole)-2,2-difluoropropylenic acid hydroxyethylamide 44 (Jt9 was obtained. m, p.

118-121.5'C.

'HN? vl R (DM S Oda);
δ ~3.30 ~4゜00 (4H, m, -C
HtCHt-0-), 5.25(2H,t,
NI CH2,J HF = 1 3
Hz), 8.1 6(l H, bs, C0
NH), 8.8 3(l)i.

s, Hs).

"FMNR (D~l5O-d6XTFA group Q); 33.
5ppm0 Production Example 4 (a) F3 NT-CH-CH, -COC,H.

Preparation of 3-nitro-1,2,4-triazole 2, 0 g (
1,8111 mol) was dissolved in dioxane 10R (
To this, trifluoromethylcrotonic acid ethyl ester 2
Add ゜39 (14meal). While heating this solution at 90°C, aluminum chloride 3,09 (23 mmo
1) gradually. After the addition is complete, add 1.
Avoid heating reaction at 00°C for 4 hours.

After the reaction, the solution was concentrated, and the concentrate was separated into chloroform and water. After drying the chloroform layer and magnesium sulfate, it was filtered and the filtrate was concentrated. The concentrate was isolated and purified by silica gel column chromatography to obtain 3-(3 2.849 °-nitro-1°-triazole)-4,4,4-trifluorobutyric acid ethyl ester was obtained.

'HNMR (CDC123): δ+=1,26(3
H,t.

-CH3, JH, "-H2" = 7Hz), 3 1
6 (I H, dd, Hta, J Hz
a ) (2b= 1 8 Hta H
tbjH+=3Hz), 3.5 8(I H,d
d, Hub, JHta Htb=
1 8 Hz, , I H+ 1-1
tb” l l Hz), 4.1 6 (2H,
Q, 0CHe, JH1” -t
”=7Hz), 0.46 (I H, m, Ilt'),
8.46 (I H, s.

Hs) = ”FMS R(CD C(!sXT F A Goko),
-4',7PpH1a (b) F3 NT CHC) ItcONHCHtcHto CH
-Production of 3-(3°-nitro-1°-triazole)-4°4.
4-1-Lifluorobutyric acid ethyl ester 2,0 g (
7. Add 40d of 6NHC12 to 1mmol) and heat at 50°C.
Heat and react for 3 hours. After the reaction, the solution is concentrated, dioxane 20R12 is added to the concentrate, and the mixture is variable concentrated.

Add and dissolve dioxane IOmQ to this concentrate, and add dionyl chloride 2, OxQc 27 mm to this solution at room temperature.
ol) dropwise. After dropping, the solution was heated at 70°C for 2 hours.
cause a thermal reaction.

2-Methoxyethylamine (3,0 ml) was dissolved in dioxane (5,0 ml), and while cooling this solution with water, the previous thionyl chloride treatment solution was added dropwise. After the dropwise addition, the reaction was stirred at room temperature for 1 hour. Concentrate the j-0 reaction solution, separate the concentrate with chloroform and water, dry the chloroporum layer with magnesium tate, filter, condense the filtrate, isolate and purify the concentrate by silica gel column chromatography, 3-(3°-nitro-1°-triazole)-4,4,4-trifluorobutyric acid methoxyedylamide 350x9 was obtained.

'HNMR(CDC(13): δ=3.13(IH
, dd.

1-La, J H1a-H2b= 1 7
Hz, J HtaH+= 3) [Z),
3.2 6 (3M, s, 0CH3)
, 3.28 ~3. 48 (3H, m, Htb
, H-"), 3.55-3.75 (2H, m, H+
″) 1.5.68 (l H, m, H,), 6,5G (I
)1. bs.

1, NH-), 8.51 (I H,s, I-TJ-
111FX~IR (CDCSXTFA standard); -4,
81) I) mfi Production example 5 NT-Ct■ tc HCHtOCHtCF tc
F 2HH 1-(2',3-epoxypropyl)-3-nitro-1
, 2,4-triazole I, 5 g (8,8 mmo
1), add 2.2.3.2-tetrafluoropropanol (15 mmol), and add 1.0 g of potassium hydroxide to this.
(181T1 mol) was added and reacted by heating at 60°C for 30 minutes.

The solution after the reaction is condensed, the concentrate is branched with methylene chloride and water, the methylene chloride layer is washed with water, dried over magnesium sulfate, filtered, the filtrate is condensed, and the concentrate is isolated by silica gel column chromatography. Purified, 1-(2゛-hydroxy-3'
-tetrafluoropropoxypropyl)-3-nitro-
1.09 of 1,2,4-1-IJ azole was obtained.

'11NMn(CDC4s>: δ=3.60~3.8
2 (3H, m, Hso-0H), 3.73-4.13
(2H, m.

-OCH,CH2-), 4.23 ~ 4.60 (3
・) [, m.

H,', I-1,'), 5.9 6(I
H, tt, -CF2H.

J p, "-p3" = 53 Hz, J Ft-F
a''~4 Hz), 8.36 (I H,s,
l-1s).

”F N'%1R (CD Cl2aXT P A standard)
;59.6ppm, 45,492m+1 Production Example 6 N'r-Cl1tCI-11''CH,OCI!3l-(
2°, 3”-epoxypropyl)3-nitro-1,2,
2.0 g (12 mmol) of 4-1 lyazole is dissolved in methanol. Potassium hydroxide l,'
09 (18 mmol was added, stirred and reacted at room temperature for 1 hour,
Further, the mixture was heated and reacted at 50° C. for 30 minutes.

After the reaction, the insoluble matter in the reaction solution was filtered, the filtrate was condensed, and the concentrate was isolated and purified using silica gel column chromatography to obtain 1-(2
To obtain 1,19 of °-hydroxy-3'-methoxypropyl) to 3-nide (7-1,2,4-triazole 1,19), this was dissolved in 10 u of dry tetrahydrofuran (!), and the solution was diluted with diethylaminosulfur trifluoride under water cooling. Drop Ride (DAST) 1.59 (9.3 mmol),
After the addition, the mixture was stirred and reacted at room temperature for 5 hours. After the reaction, 2 oz (l) of water was added to the solution, the excess DAST was removed, the solution was concentrated, and the concentrate was isolated and purified by silica gel column chromatography, and 1-(2°-blue 3°-methoxypropyl) was added. -3-nitro-1,2,4-1-lyazole 420 shoulder 9 was obtained.

'HNMR (CDCf2 δ-3,48 (3H, s.

-OC+-1,), 3.58 (211dd, H, °, J
l-1. °−! ■3' = 4 Hz, J + (3
F = 6 Hz), 4.08~4゜42 (2H, m
, I(+'), 5.15(IH,dm, -CHF
-, J H3' F = 4 7
f(z), 8.3 2 (I H.

s, H,).

"FNMR (CDC (!aXTFA standard), +13°
ppma Production Example 7 N T CHt CHF CHt OCOCH3l-
(2°,3°-epoxypropyl)-3-nitro-1.
Add 50 x 2 of glacial acetic acid to 4.29 (25 mmol) of 2.4-triazole, and heat the reaction at 70°C for 12 hours. The solution after the reaction was concentrated, and 1.8% of +-(3°-acetoxy-2°-hydroxypropyl)-3-nitro-1,2,4-triazole was purified by silica gel column chromatography.
99 (8.21 mmol) was obtained.

To this, add dry tetrahydrofuran*O:J (l) and completely dissolve, and under water cooling, add 2.0 g (12.4 mmol) of diethylaminosulfur trifluoride (DAST).
was added dropwise, and after the dropwise addition, the mixture was stirred and reacted at room temperature overnight.

Add 2 Oyt(l) of water to the solution after reaction, and add excess D
After treating AS'r, the solution was condensed, and the concentrate was isolated and purified by silica gel column chromatography to obtain 1-(2°-fluoro3°-acetoxypropyl)-3-nitro-1,2,
4-triazole 463H was obtained.

'HNMR (CDC12s): δ=2. I 5 (3H
,s.

-COCH3), 4.28-4.88 (4H, m, H,
”.

H5'), 5.12 (I H, dm, Hz', JF=
46.6Hz), 8.32 (IH, s, Hs).

"PNMR (CDC123XTFA standard); 113°
99m6 Production Example 8 N T CHt CHF CHv OHl-(2°-
Fluoro-3°-acetoxypropyl)-3-nitro-
1.2.4-triazole 420 JH9 (1,81m
2N) Ic12 was added to the mixture (mol) and stirred overnight at room temperature.
After concentrating the reaction solution, it was isolated and purified by silica gel column chromatography to obtain 1-(2'-fluoro-3-hydroxypropyl)-3-nitro-1,2°11-triazole 23
I got 0JI9.

' HNMR (CD CQ 3 ): δ=3.5
8-4. I5 (2H, m, Hl, H3'), 4.44 ~
4.68 (IH.

m, Hta'), 4.72-4.85 (IH, m, Hu
b'), 5.0 2 (I H, dm, summer-L'
, JH,”-F=4 8.2Hz), 8.3
0(l H,s, H-).

"FNMR (CDC (!3XTPA standard); 115°4
ppm.

Production example 9 N T CHt CH= CHOCHt CP s2
．． 2.2- Trifluoroethanol 1691ρ (27
Mix 5.0 x (1 mmol) of dioxane and 1.09 (18 mmol) of potassium hydroxide.

While heating and stirring this solution at 60°C, I-(2'
, 3°-epoxypropyl)-3-nitro-1,2,4
A solution prepared by dissolving 1.5 g (8.8 mmol) of -triazole in dioxane 5, O, =Q was added dropwise over about 10 minutes, and after the dropwise addition, the reaction was continued with heating for an additional 20 minutes.The reaction solution was concentrated to form a concentrate. The methylene chloride layer was washed with water, dried over magnesium sulfate, filtered, the filtrate was concentrated, and the concentrate was isolated and purified using silica gel column chromatography to obtain I-[3'-( 2”, 2”.

420 m9 of a mixture of cis and trans isomers of 2''-trifluoroethoxy)-2°,3'-propenyl]-3-nitro-1,2,4-triazole was obtained.

Cis body 1 summer 4N M R (CD C≦!.); δ=4.28
~4.56 (2H, m, H,'), 4.73 (2H, q
,H,”,JHr”c Fs=9 H2),5.
68 (I H, dt, H1'.

J H1'Hl" = 9 Hz,
J H+° Hs' = 6 Hz)
, 6.74 (IH, dt, H3°, J Hr' -H
3'=9Hz.

J Hl′ −Hs”, = 6 Hz), 7.92(
l H,s, Hs).

"FNMR (CDC12s) (TFA standard); -4,
6ppm.

Trans form 'HNMR (CDCI23): δ=4.28-4.5
6(2H,m,H,′), 4.73(2H,q,H,”
, JCF x = 9 Hz), 6.42 (I H, d
t, H3°, JH*=14HzSJH,'=5Hz)
, 7.00 (I H, dt.

H,'JHt'-Ht'=14Hz, JHt'-
Ht” = 2Hz), 7.92(IH,s,)(s)
.

"F NMR (CD C123XT FA standard); -
4,5ppIIl.

Production example 1O NT-CF=CF-CF.

3-nitro-1,2,4-triazole 3.09 (26
mmol) and sodium carbonate 7,09 (66 mmol
) in dimethylformamide 75J! (Dissolved in!, 6
- The reaction was allowed to stir overnight at room temperature under a stream of propene fluoride.

After the reaction, the solution was concentrated, the concentrate was separated between chloroform and water, the chloroform layer was dried over magnesium sulfate, filtered, the filtrate was concentrated, the concentrate was isolated and purified by silica gel column chromatography, and I-( 1', 2°.

3゛, 3°, 3゛-pentafluoropropenyl)-3-
Nitro-1,2,4-triazole 153 and l-1
°, 2°, 3°, 3°, 3′-pentafluoropropyl)-3-nitro-1.2.4-triazole 6701 g
I got it.

! -(1°, 2°, 3°, 3°, 3'-pentafluoropropenyl)-3-nitro-1.2.4-triazole is a mixture of cis and trans isomers' HN M R (CDC (I3): δ=8.5
8 (I H, s.

tls) lgFN~IR (CD CC*XT F A-A11)
;67, Oppm, 20.6ppm, I l
, 2ppm.

Trans isomer' HN MR (CD CC3); δ = 8.
6 9 (I H, s.

H5) ``P NMR (CD C (!+XT F A language):'
8. ), 2ppm, 48.2ppm, IO,9
ppm.

■-(1°, 2', 3°, 3°, 3°-pentafluoropropenyl)-3-nitro-1,2,4-triazole'HNMR (CDCC,): δ = 5.31 to 6.1
0(l H, m, Ht'), 8.7 4
(I H, d, Hs)”FNNIR(CDC
123XTFA loss), 131°7ppm, 23.
9ppm, 7.5ppm, -4.7ppm.

Il,! Example 11 N T CF t CF! H s-nitro-1,2,4-triazole 1.09 (88
mmol) and sodium carbonate 2.0g (19mmol)
was dissolved in dimethylformamide 25x0-, and a reaction was carried out by heating at 100°C for 5 hours under a stream of 4-fluoroethylene. After the reaction, the solution was condensed, the concentrate was separated between chloroform and water, and the chloroform layer was dried over magnesium sulfate,
After filtration, the filtrate was condensed, and the concentrate was isolated and purified using silica gel galam chromatography.

318 u of bi,2′,2°-tetrafluoroethyl)-3-nitro-1.2.44 riazole were obtained.

'HNMR (CDC12*): δ = 6.54 (
I H, u.

H,', JHt-F! '=52H2, JHt-F
,'=4[(z).

"F NS [R (CD (J!3)) (TFA standard)
;58.5p, pms 22, , ) ppm Production Example 12 NT CHt CHC (t F OH 1-(2',3'-epoxyprobyl)-3-nitro-
1.2.4-triazole 1.111j (6,52m
MoI) was dissolved in 100 ml of dioxane (100 ml of dioxane), and while stirring this solution at room temperature, 2.0 ml of pyridine hydrofluoric acid salt (Oller's reagent) was added, and the reaction was continued with stirring for 1 hour.

Calcilyl carbonate (2.09 g) was added to the reaction solution, and the resulting precipitate was filtered. The filtrate was condensed, and the concentrate was purified by silica gel column chromatography. Solvent: chloroform/methanol), I-(3'-fluoro-2°-hydroxypropyl)-3-nitro-1°2.4-triazole (340 yg) was purified by silica gel column chromatography. Obtained.

'HNMR (CDCC3): δ=4.36-4.7
0 (3H1 Chiku, 1■1°, H,') 4.51 (2H, dm, H3°, J T-13'
F = 47 Hz) 8.34 (+1-1.S, H5) lllFNNIR (CDC (!zXTPA standard) 15
3 ppm Production Example 13 NT-CH, CF2CH20H (25) 3-(3°-nitro-beetriazole)-2°2-difluoropropionic acid 2,0 g (9,0 mmol) in THF 30 m
Add N to the +7 solution while cooling to -70°C under a nitrogen stream.
aBHal, '00g (26.4 mmol) was slowly added. Add BFsO(CyHs)+2, 5m
(!(20.2 mmol) of 'I'' HP I Om (solution) was added dropwise while cooling in the same manner, and the reaction was further stirred for 1 hour.

After the reaction, while cooling the solution with ice water, add 25 m of ethanol.
After adding & to deactivate the excess reducing agent, the solvent was distilled off. The concentrate was separated with ethyl acetate/saturated brine, the ethyl acetate layer was dried over magnesium sulfate, filtered, the filtrate was concentrated, and 11 products were isolated and purified using a silica gel column.
(2',2°-difluorohydroxyprobil)-3
5501 g of -nitro-1°'2,4-triazole was obtained.

'HNMR (CDC12,l): δ=2.97(I
H,t.

-OH, J=6.511z), 3.89(2tl, d
t, II+”.

JH,・0H=6. 5 H2, J H3
p=13Hz), 4.84(2H,t,)(+'
, J H, ·-p = 13 Hz), 8.36 (I
H, s, Hs) "FNMR (CDCQ3XTFA standard): 33.Op
pm Production Example I4 NT-CH,CHFCNHC)-[IC1120CH3
5101 g of methyl 3-(3-nitro-1°-triazole)-2-fluoropropionate and 20 mf of dioxane
830x9 of methoxyethylamine was added to the 2 solution, and the mixture was stirred at room temperature for 5 hours. After the reaction, concentrate under reduced pressure and atlN
The product was purified using a silica gel column. 3-(3°-
Nitro-]°~triazole)-2-fluoropropionic acid methoxyethylamide 390π9 was obtained.

'HNMR (DNISO-d,): δ=5. l0(2
H.

d, d, H,', JHI H, °=4Hz, Jl+,'
-F=2 4 H2), 5.5 6CI H,d
, L H,' , J t1. 'H
, l =4 Hz, J H4F =4 8
14z), 8.75 (I H, s) "F-NS=IR (DNISO-da) (TFA group Q)
:116.7ppm Manufacturing example! 5 NT CHtCFtCHt NHCCIlo
(40) 3(3°-nitro-1-triazole)-2,
2-difluoropropylamine 1.21g THF50
To the mρ solution, add 1.0 g of acetic anhydride and 1.0 g of pyridine.
was added and stirred at room temperature for 2 hours. After the reaction, THF was distilled off under reduced pressure, and the concentrate was purified using a silica gel column.
-(3°-nitro-1-triazole)-2,2-difluorobropyruacetamide 720JI9 was obtained.

Melting point: 126.5-128.2°C.

'HNMR; δ=2.08(3H,s), 3.88(
2H,dt, H,', J 1.1-p
= I OH2, J H,' -N16Hz)
, 5.1 G(2H,t, JHF=1 6
H2), 8.6 0(I H,t, )INII
, J1-INII-Ll3゛=6)! z
), 9, + 2 (I T4.s) "FNMR, (111SO-da TFA standard); 2
s, 5ppm Production Example 16 NT-CI-12CrtCI-1, N'11CC82C
)1tOtl(II) 3-(3°-nitro-1-triazole: l-2,2-
Nofluoroprobylamine l, 0.1 g 'I'
1.37 g of β-propiolactone was added to 50 ml of 11 F solution, and the mixture was reacted at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in 200 ml of ethyl acetate (!) and washed with water. After drying over anhydrous magnesium sulfate. , filtrate, concentrate the filtrate, and purify the concentrate on a silica gel column to obtain 3-(3
゛-Nitrol-1-triazole)-・2,2-difluoropropyl-(2″-hydroxypropio)amide 28
Obtained 0xg.

Melting point j02.0-I04.0'C.

) (NMR (DMSO-da): δ-2,54(2
H.

t, l-1, ·, JH, ·-〇, ·=7Hz), 36
0-4.00 (4H, m), 5.50 (2+-1,
t, JHF=16H2), 8.52(I I(,
t, HNH, J I-I NH-H, + = 6 Hz
), 9.0 0 (I H,s)”FNMR (DMSO-d,, TFA standard): 28,
1 ppm Production Example 17:1 NT-CHtCFtCNI-1i (43)3-(3
20.0 g (80 ml 1111 l) methyl °-nitro-1-triazole)-2,2-difluoropropionate
200ml of 10% ammonia-methanol solution was added dropwise to the methanol roomc solution. After the dropwise addition, the mixture was stirred at room temperature for 3 hours, and after cooling, the precipitated colorless crystals were filtered off.

The colorless crystals were recrystallized from methanol and 3-(3'
-Nitro-1-triazole)-2,2-difluoropropioamide + 6.6 g was obtained f2.

Melting point 1116.0-147.5'c.

'HN~rR (D NIS 0-de): δ
= 5.24 (2H.

t, J 1.1-F = I GHz), 8.2
5 (I H, br, s), 13.44 (I H, b
r, s), 9.00(l H, S)"F -NX1l
l (DXIS O-d, XTFA standard): 30,
8 ppm Production example 18 XT CHtCFtCH*NHt (39) 3-(
A solution of 8.8 g (39.8 mmol) of 3°-nitro-1-triazole)-2,2-difluoroprobiamide in 100 m of dry THF was added under a nitrogen stream while cooling with water.
Hydrogen f Sodium Boronate 4.52g (119 pieces of)
Add <C) to 几. To the resulting R5 suspension, 13F
, ・Ether complex 16.1m0.4') Tetrahydrofuran 50mf! The solution was added slowly with water cooling. Stir for 4 hours while cooling with water, and further stir for 4 hours at room temperature. After that, the reaction solution was poured into water, diluted hydrochloric acid was added to make it acidic, and the mixture was stirred for 2 hours. To this aqueous solution, add an aqueous potassium hydroxide solution to make it alkaline, and then extract with ethyl acetate.

The extract was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified using a silica gel column to obtain 3-(3''-nitro-1-1 riazole)2.
．． 2-Nofluoropropylamine 98019 was obtained.

'II-? <XIR(I)Nls o-ds): δ
= 3.08 (2H, t, J HF = 15 Hz)
, 5.0 G (2H, t, , l1lF131-1z
), 8.97(l l-1,3)19F-NXIR(D
MSO'dJ ('I''FA standard): 30.3 ppm Production example 19 N'1-CHtCP, CNHOH (44) 3-(3°-
Hydroxyamine hydrochloride was added to a solution of 1.88 g of methyl nitro-1-triazole-2,2-difluoropropionate in 50 ml of methanol! .

=tg was added. Add 0.4 g of potassium hydroxide to this solution.
A solution of 50 mQ of methanol was slowly added.

After the reaction, concentrate, dissolve the concentrate in 100 ml of ethyl acetate, wash with water (50 m (! 07 g of 3-(3'-nitro-1-triazole)2,2-difluoropropionic acid hydroquinamide was obtained f2.

"HNXIR (heavy acetone): δ = 3.32 (IH.

S), 5.28 (2H, t, Jl-I P=15Hz
), 873 (I ) [, 5) 19r" NMR (ffi acetone); 33.4 ppm Production example 20 !l -1- N T CHt CF t CN HCHt CHt
NHz CQ3-(3'-nitro-1-triazole)-2,2-difluoropropionate methyl 5. OOg
Add 5.0 ethylenenoamine to 30 ml of THF solution. Og
added. After reacting for 2 hours at room temperature, it was concentrated under reduced pressure, and hydrochloric acid was added to the concentrate to obtain 3.2 g of 3-(3'-nitro-l-triazole)-2,2-nofluoropropionic acid ammonium ethylamide hydrochloride. I got it.

'HNMR (DMS Oda): δ = 3.40 ~ 3゜58 (4H, m), 5.34 (2H1t, JHp
= 1 GHz), 9.13 (114, s) ”P NMR (DMSOJgXTFA standard): 31.
4ppm Production example 21 NT-CH2CFtCH, NHCH, CHf0CH33
(3'-nitro-1°-triazole)-2°2-
difluoropropionic acid methoxyethylamide l,
A 50 mC solution of 25 g (5 mmol) of dried diglyme was cooled with water under a nitrogen stream, and this solution was added with N a B 8
40.

33 g (l Ommol) was added, and while continuing water cooling, 1.8 m12 (13.5 mm
A solution of 30 mg of diglyme (30ml) was slowly added dropwise to the mixture, and the mixture was stirred for 2 hours while cooling with water, and further stirred for 4 hours at room temperature. The reaction solution was slowly poured into diluted hydrochloric acid, then made alkaline by adding an aqueous sodium hydroxide solution, and then extracted with ethyl acetate.

After drying over anhydrous magnesium sulfate, it was filtered, the filtrate was concentrated, and the concentrate was purified using a silica gel column to obtain 3-(3°-
0.1 g of nitro-1°-triazole)-2,2-difluoroprobyl-methoxyethylamine was obtained.

'HNMR (DMSO-da), δ-2,81 (2H.

t, LI A , , 1 1. IA
I-IB=5)+2), 3. 1 2 (2H, t.

' +-I P = 1 5 + (z),
3.3 0(3[4,s), 3.42(2H,t
, HB, J) [AI-[B = 51-1z
), 5.08 (2t, Jli p=I 511z),
9.00(l I-1,S)"F NMR (DMSO
clsXTFA basics) = 27 language ppm Production example 22 N T CHt CHF CN HCHt CHt
OH3-(3°-nitro-1"-triazole)-2-
Methyl fluoropropionate 5101119 was dissolved in 20ml dioxane, hydroxyethylamine 830ml
The mixture was stirred at room temperature for 5 hours. After the reaction, it was concentrated under reduced pressure, and the concentrate was purified using a silica gel column to obtain 3-
(3'-nitro-!'-1-lyazole)-2-fluoropropionic acid hydroxyedylamide 310iy
I got it.

'HNMR (DMS 0-da), δ=5.10 (2H
,d,d,HA,JHA-HB=4H2,
JH-p=24Hz), 5.60(l H, d, t,
HB,, 1HA-JIB=4 Hz, JH-p=4
8Hz), 8. ．． 8 0(l)[,s)”F
NMR (DMSOdsXTFA standard): 116,
0 ppm(-) Production example 23 NT CHt CF t CN HCHt CH3(
48) 3-(3°-nitro-1-triazole)-2,
50 g of dioxane solution of 2.369 methyl 2-difluoropropionate (7 with ethylamine (70%) I m
(Added l.

After the reaction, it is concentrated, and the concentrate is purified using a phosphoric gel column.
1.789 of 3-(3'-nitro-1-triazole)-2,2-difluoropropionic acid ethylamide was obtained.

Melting point 69.3-710°C.

'HNMR (DNISOde, TMs basis): δ-1,
+ 7 (3H, t, J) 1. ”-H,”-8
Hz), 3.31 (21-1 quint, J
+-1r″-82-= 6 Hz), 5.3f3 (2H
,t, JHP=l 5Hz), 9.12(2
H, m).

“F-NNIR (D?vlSOds, TF, AM quasi);
31. 3 ppm (t,, I MF =
l5)! 'z).

Production example 24 NT C1-1tCFzCNHCIItCIItCI
Ii (-19) Methyl 3-(3-nitro-1-triazole)-2,2-difluoropropionate 2.36
9 dioxane solution 50J112 and propylamine 0.
659 was added.

After the reaction, it was concentrated, and the concentrate was purified using a silica gel column.
3-(3'-nitro-1-1 lyazole)-2,2-difluoropropionic acid normal propylamide 1.50
I got g. Melting point: 66.0-68°7°C.

' HN M R (D M S O-ds, T M
S standard): δ=0.94 (3H, t, J H, -H
, -=6Hz), 1.53 (2H, 5ext, J
H+''Ht' = J Hz” 8
3″ = J)!, -NH = 6 H2),
3.24 (2H, Q, JH2"H3" = JH
,''NH=6Hz), 5.3 7(2H,t.

JHF=15Hz), 9.12 (2H, m).

"F NMR (DiVIS Odo, TFA standard): 30.9 ppm (t, JHF=I5Hz).

Production example 25 N71'-CHtCFtCNH(CHt)sCH, CD
0) 3-(3°-nitro-1-triazole)-2
, 8 g of n-hexylamine was added to 50 g of a dioxane solution of 2.369 methyl 2-difluoropropionate.

After the reaction, condensate and purify the concentrate with a silica gel column,
2.19 of 3-(3'-nitro-1-triazole)-2,2-difluoropropionic acid hexylamide was obtained.

Melting point 73.6-75.8°C.

'HNMR (DMSOds, TMs standard); δ=0.9
6 (3H, t, JH, -H,"=6Hz), 1.10~
1.70 (8H, m), 3.24 (2H, q, J H
z″-H,″=7Hz), 5.3 3(2H,
tl, I HF = I 5Hz), 9.10 (2
H, m).

”F NMR (DMS Ods, TFA standard);
30.8 ppm (t, J HF = 1 5
Hz).

Production Example 26 1: NT-CtltCF2C:';I-ICHICF 3
(51) 3-(3'-nitro-1-triazole)-
A solution of 2.369 methyl 2,2-difluoropropionate in dioxane a 50 , q (2) was added with 209 grams of trifluoroethylamine hydrochloride, and while stirring vigorously, 1.59 grams of triethylamine was slowly added dropwise.

The solvent was distilled off, the residue was dissolved in 200M ethyl acetate, washed with water, the ethyl acetate solution was dried with magnesium sulfate, concentrated, and the concentrate was purified using a silica gel column.
3-(3”-nitro-1-1-lyazole)-2,2-
1.6 g of fluoropropionic acid trifluoroethylamide was obtained. Melting point: 103.5-105.5°C.

'It-NMR (DMSO-d, T~IS standard): δ
=4.08(2)Lm), 5.40(2H,t,JHF
=l 5 to 1z), 9.90 (LH, s), 9.8
1 (IH, t, JI-I, -tINH=6) [z)
.

"F-NSIR (DMSO-da, TFA group Q) knee 8
．． 1(3F, t, JHF=l 0f(z), 30.7(
2F, t, J Hr' = l 4 Hz) Production Example 27): NT-CH2cFtcN]-[(CHy)3CFt
(,)2)3-(3°-nitro-1-triazole)-
To a solution of 2.36 g of methyl 2,2-difluoropropionate in oxane was added 2.5 g of trifluorobutylamine hydrochloride, and 1.5 g of triethylamine was slowly added dropwise with vigorous stirring.

The solvent was distilled off, the residue was dissolved in ethyl acetate at 200 °C,
After washing with water and drying the ethyl acetate solution with magnesium sulfate, the 611M product was purified using a silica gel column.
-(3°-Nitro-1-triazole)-2,2-difluoropropionic acid trifluorobutyramide 1.89
I got it. Melting point 58.3-61.5°C.

'H-NNl R (DMSOde, TMs standard);
δ = 1.40-2. G O (41-1n), 3.
23(2+(,q.

J) I, -iI 2'' = 7+1z), 5.
2 8 (21-1, t, JtlF=I 5 Hz),
9.02 (l I-1, s), 9.12 (I +-1,
t.

, IHs--)-1, -=511z).

Same F-N ~ IR (DMS O-d,, 'I' F A standard) Knee 13.5 (3F, t, J!IF=121-1z
), 31.0 (2F, t, J HF = l 5
)IZ).

Production example 28 NT CHzCFtCNHCH(CHs)t (5
3) 3-(3°-nitro-1-triazole)-2,2
- Add 0.659 g of isopropylamine to 50 g of a solution of 2.369 g of methyl difluoropropionate in dioxane.

After the reaction, condensate and purify the concentrate with a silica gel column,
224 g of 3-(3'-nitro-i1-riazole)-2,2-difluoropropionic acid isopropylamide were obtained. Melting point 83.8-86. PiC0'HNMR (DMS
Oda, Tlvls standard): δ = 1.20 (6[-1,
d, JH3-Hz-=6Hz), ・1.08 (I
I(,m), 5.3 6(2[(,t, J H
F = I 5 Hz), 8.94 (lH, d
, JH,″ −H,″ = 8Hz), 912(
IH,s).

19F NVn (DMS Oda, T F AWQ)
; 31, o(t,, + HF = 15 Hz)
.

Production ρR1 i<T CHtCF tcNHC(CH3)3 (
54) 3-(3'-nitro-1-triazole)-2,
2 = 2.00 g of thionyl chloride was added to a dioxane solution of 2.22 g of difluoropropionic acid, and the reaction was carried out at room temperature for 2 hours. To this, 5 mQ of tertiary butylamine was added, and the reaction was further carried out.

The reaction solution was dissolved in 200ml of ethyl acetate and washed with water.

After drying the ethyl acetate solution with magnesium sulfate, it was concentrated.
The concentrate was purified with a silica gel column and 3-(3'-nitro-1-triazole)-2,2-difluoropropionic acid was obtained to obtain 1.2 g of monobutylamide, f:o melting point 60.5.
~630℃.

'! (-NMfl(DMSO-d,, TMS base):
δ=1.40(91-1,s), 5.3 0(21
(, t, J HF = 1 4Hz), 8
．． 3 6 (br, s, N)D, 9.07(l
H,s).

laF-NXIR (DMSO-d, TFA standard): 3
0, I ppm (j, J l−I P = 14
Hz).

Production Example 30 Add 0.859 cyclopropylamine to 50 mQ of dioxane solution of 2.369 methyl 3-(3°-nitro-1-triazole)-2,2-difluoropropionate and add 7
two.

After the reaction, it was concentrated, and the concentrate was purified using a silica gel column.
3-(3'-nitro-1-triazole)-2,2-difluoropropionic acid cyclopropylamide 2.049
I got it. Melting point 114.6~II66°C0'H-NλI+1 (D\l5O-d8.T~IS standard)
; δ=0, 50 ~ l, 0 0 (4H, m),
2.90(I)1. m), 5.36(21(,t,
JHF=15Hz), 9.1.3(+H,s).

"F-NMR (DMSOds, TFA standard); 30.9
(t, JHF = 1 5Hz).

Production Example 31 NT CHtCFtC>;H(CHt)tOcHtc
H3(56)3-(3“-nitro-1-triazole)
Methyl -2,2-difluoropropionate 2.3 G9
To 50ml of a disoxane solution (1) was added 6g of ethanolamine ethyl ether.

After the reaction, it was concentrated, and the concentrate was purified using a silica gel column.
3.1 g of 3-(3°-nitro-1-triazole)=2,2-difluoropropionic acid ethanolamide ethyl ether was obtained. Temperature: 70.0-71.5℃.

'H-NMR (DSISO-ds, TMS group Q); δ-
1,19 (3H, t, JHl--■,-=8Hz), 3
．． 22-3.70 (6H, m), 5.32 (2L1.t
, Jl-IF=14Hz), 9.0 8(IH
,s), 9. 1 2 (I H, t.

J t1, ″−H1″ = 6Hz).

"F-NMR (DMSO-d8.TF, A group Q): 31
．． 0 (t, JHF=14Hz).

Production example 32 i NT CHtCFtCNtl (CHt) 30cI (2
c113 (07) Methyl 3-(3°-nitro-1-triazole l-2,2-difluoropropionate 2.3
Add 2.09% of propatoolamine ethyl ether to 50R0 of the dioxane solution of No. 69. After the reaction, concentrate and purify the a-condensate with a silica gel column.
2.56 g of 3-(3°-nitro-1-triazole)-2,2-difluoropropionic acid propazuramide ethyl ether was obtained.

'H-NMR(DMS O-de, T
MS standard); δ=1.10 (3H, t, JH, --
H3″=6Hz), 1.G8(2H, quint, J
Hz″-H3″ = 7Hz), 3.10~
3.60 (6H, m), 9.00 (IHLs), 5.3
6(2H,t,JHF=l 5Hz>.

”F NMR (DMS O-ds, TFA standard)
;31.1 (t, Jl-IF=l 5Hz).

Production Example 33 5T-CHtCF, CNH(CHt)30cH3(58
)3-(3°-nitro-1-triazole)-2,2-
2.30 g of methyl difluoropropionate in a solution of 50 ml of methyl difluoropropionate, preferably 1.3 ml of propatoolamine methyl ether
49 was added.

After the reaction, it is concentrated, and the concentrate is purified using a phosphoric gel column.
2.97 g of 3-(3°-nitro-1-triazole)-2,2-difluoropropionic acid propatoolamine methyl ether was obtained.

'H-NMR (DMSO-d, TMS standard); δ=1
．． 80(2H,t,J)i, ″−H,″ = 7H
z), 3, 20-3.60 (7H, m), 5.3
6 (2H, t, JHF=15Hz), 9.08 ppm
(2H, m).

"F NMR (DMSOdo, TFA standard); 31.
2 (t, Jl-IF=I 5Hz).

Production example 34 NT CIItCFtCNH(CHt)sOH(
59) 3-(3°-nitro-1-triazole”)-2
, 2.369 methyl 2-difluoropropionate in dioxane solution 50.117+ to propatoolamine 1.8
g was added.

After the reaction, the a-condensate was purified using a silica gel column,
1.99 g of 3-(3°-nitro-1-1 lyazole)-2,2-difluoropropionic acid propazoleamide was obtained. Melting point: 97.0-99.6°C.

'Hi', MR (DMSOde, TMs group Q); δ=1
．． 60 (2H, m), 3.00-3.60 (41 (
, m), 4.50 (I H, s), 5.24 (21-(
, j, JI (F=15t[Z), 9. 00(I)(
, s).

19F NMR (DMS Oda, TFA group Q)
; 30.9 (t, JI-IP=l, +H2).

Production Example 35 0 0H 1: NTCHt CF 2 CN1-I CHt Cr(C
I-13(60) Methyl 3-(3°-nido[1-1-triazole)-2,2-nofluoropropionate 2.3
69 dioxane solution to 50 liters of propatoolamine 1.
89 was added.

After condensation, the concentrate was purified with a silica gel column and 3-(3'-nitro-1-triazole)-2,2-
Difluoropropionic acid isopropanolamide f, 8
To obtain 2g, melting point 110.0-112.88C0'H-NNIr ((D, tlSO-da, TMs standard)
:δ=1.0 8(3H,d,Jl-1,″-H,
″ = GHz), 3.19 (2+-[, t, JH
,--NH=6Hz), 3.80(+H,m), 4.8
4(lH,d,JH,--1-r,''), 5.34(2
H, t, JHF=14Hz), 9.08 (2H, m).

”F NMR (DMS O-da, TPA-based)
;30.9(t, Jl-(F=14Hz).

Production example 36:) NT-Cl-1tCP tc NH(CHt
) to (CHt) to H (61) 1.56 g of diglycolamine was added to a solution of 2.369 methyl 3-(3°-nitro-1-triazole)-2,2-difluoropropionate in dioxane (m50if2). .

After the reaction, the concentrate was purified with a silica gel column to give 3-(3'-21-rho-1-triazole)-2,
2-nofluorobrobionic acid diglycolamide 2.0
6g was obtained. Melting point: 74.5-77.0°C.

'H-NMR (D\ISOds, TMS standard): δ=3
．． 30-3.70 (81 (, m), 5.3 G (2+
−1, t, JHF = I 5 + (z),
-1,70 (l H,s), 9.09 (21
(, m).

"F-NMR (D ~ [S 0-da, TF A standard);
31.0 (t, JHF=15Hz).

Example 1 Radiosensitization effect in cells (E Rin vitro
) In order to examine the radiosensitizing effect of the compound (1) of the present invention on V-79 Chinese hamster cells, V-79
100,000 cells were cultured in a single layer in a glass petri dish,
V-79 cells were prepared in logarithmic phase.

A medium solution of the test compound at a predetermined concentration was added to a Petri dish, left to stand at 37°C for 60 minutes, then placed in a sealed container at room temperature, and nitrogen gas was passed through it for 10 minutes to eliminate oxygen.
To irradiate X-rays at a dose rate of y/min.

After irradiation, the cells were washed with phosphate buffer, made into single cells with trypsin, and then placed in a culture dish using medium 51! Q
The cells were cultured at 37°C for 7 days, washed with water after staining, and the number of colonies produced was measured.

The results are shown in the following table as ERinviLro.

Example 2 Radiosensitizing effect on animal transplanted tumors (ERin vivo) 10' EMT-6 tumor cells were subcutaneously inoculated into the thighs of both legs of 13alb/C male mice (8 weeks old, 4 mice in - group). . After tumor cell inoculation, when the size of the tumor reached the diameter of IC thorn, a physiological saline solution of the test compound was administered intraperitoneally (200 x 9/kg), and 40 minutes later, 450 radZ was administered.
The mice were irradiated with X-rays for 5 min, and the mice were sacrificed 5 min after irradiation.

After whole body sterilization with 70% ethanol, the tumor area was excised, the tissue was chopped, mixed with trypsin 22IRQ, and stirred at 37°C for 50 minutes. Take the supernatant, count the number of cells, and spread a predetermined amount onto a plastic plate with a diameter of 5Cl.
After adding medium 52112, the cells were cultured in a carbon dioxide gas incubator, and the cells that were irradiated with X-rays were removed from the incubator after 9 days, and the cells that were not irradiated with X-rays were removed from the incubator after 10 days, and the cells were fixed with methanol. Stain the cells with a staining solution and count the number of colonies formed.

Cells that were not irradiated with X-rays were used as a control, and the survival rate was measured. The results are shown in the following table as ERinvivo.

Among the nitrotriazole derivatives, the compound (13) where R=-CH2CH-CH,Q H and the comparative compounds (1) and (2)
When compared with, the compound (13) where Q=P is compared with the comparative compound (13) where Q is a pond halogen (Br or C&).
Compared to 1) and (2), lower capacity and equivalent Inviv
o sensitizing activity (ERin-vivo) is expressed.

Furthermore, among the fluorine derivatives, compounds (13) and (2)
When compared, compound (2) has higher activity (ER = 1.49 (50 mg 1 kg)) and lower toxicity (1, D 50 > 3, 0 g/&g) than compound (13).
I'm at t.

As mentioned above, among halogen-substituted compounds, fluorination significantly increases activation and decreases toxicity.

Production example 37 N T CH2CF t CN HCHt CII
tCN H21-(3'-nitrotriazolyl)-2
, 2-nofluorobrobionic acid methyl ester 2.00
y (8°47 mmol) was dissolved in 20 i of nooxane (!), and β-alanine methyl ester hydrochloride 1.50 g (1
0.7mm01) and further potassium hydroxide 2.0
0 g (35°6 mmol) was added, and the mixture was stirred and reacted at room temperature for 30 minutes.

After the reaction solution was decanted to remove insoluble matter, it was concentrated, the concentrate was separated with ethyl acetate/water, the ethyl acetate layer was dried over magnesium sulfate, filtered, and concentrated to give 1
-(3″-nitrotriazolyl) ~2°,2′-nofluoropropionic acid-3-alanine methyl ester (A)
2.20g was obtained.

This compound (A) 1,809 (5,861111110
20 m of saturated ammonia methanol solution (!) was added to 1), and the reaction was stirred for 3 days and nights at room temperature. The solution after the reaction was concentrated, and the concentrate was isolated and purified by silica gel column chromatography to obtain the title 1-(3”-nitro triazolyl)-2
°,2'-difluoropropionic acid-3-alanylamide 437H was obtained.

'IINMR (DMSO-da): δ=2.40 (2H
,t, -C14,Co-.

J=711z), 3.30 3.58(2H,m,
NHCl+2. 5.32(28,t, CtlzC
Ft, J=15Hz), 7.0O(ill, bs.

-C0NHt), 7.50(LH,bs, -C0
NI1. ), 9.09 (lit, s.

Hs), 9.14 (lit, t, C0NII,
J=6Hz)”FNl+lR(DMSOdeXT F
A group Q): 31. ippm production example Production example T-CH, CHFCH, oct-r, ct+, oct
Add 20.89 (0.27 mol) of methylcellosolve to 25 g (0.27 mol) of t3 epichlorohydrin, add 0.1 mQ of concentrated sulfuric acid, and incubate at 100°C.
The reaction was heated for 0 hours. After the reaction, ether 500JI (
! was added, and the mixture was washed with saturated aqueous sodium bicarbonate and saturated brine. The ether layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to obtain 1-chloro-2-hydroxy-3-(2°-methquinethogin)propane 209.

111 NMR (CDC1,): δ-3,40 (311
, S, -0CH3), 3.45-3.82 (911, m
, +1. , +12. ! 1. ' , II2°, -011)
, 3.84-4.18 (1, m, 1 it) l-chloro-2-hydroxy-3-(2°methoxyethoxy)propane (18 g C0, I l mol) was dissolved in 300 m9 of dioxane, and potassium hydroxide was added to this. 6゜2
9 (0, 1 mol) was added, and the mixture was heated and reacted at 70° C. for 2 hours. After filtering the reaction solution, the filtrate was concentrated and 3-(2
゛-Methoxyethoxy)-1,2-epoxypropane 6
I got g.

'IINMR (CDCQ3): δ = 2.60 (IH,
dd, Il, a, J,,,b=711z.

J = 4Hz), 2.82 (IH-dd, lI, b.

11゜J,,,,=711z,J,,,=511z)3
．． 06-3.30 (LH, m, L) 3.40 (311, m, -0Ctla) 3.46-4.
00(611,m,H3,Il,',llt')3
-(2'-Methoxyethoxy)-1,2-epoxypropane 2.09 (15 mmol) and 3-nitro-1°2.
Add 2.09 (18 mmol) of 4-triazole,
The reaction was carried out by heating at 0°C for 3 hours. After the reaction, 50 g of ethyl acetate was added to the solution, and the mixture was washed with saturated brine.

After drying the ethyl acetate layer over magnesium sulfate, it was filtered, the filtrate was concentrated, and the concentrate was isolated and purified by silica gel column chromatography to obtain 1-[2"-hydroxy-3°-(2
“-methoxyethoxy)propyl-3-nitro-1,
1.8 f/2,4-triazole was obtained.

'IINMR (CDCC3): δ = 322 (3H, s,
-0C113), 3.50-3,91 (7H9I11,
113°, II, ", It", -011), 4.10 ~
4.32 (lit, m.

It'), 4.38-4, 52 (211, m,
t(%), 8.43(ill, s, Ha)l-[2
°-Hydroxy-3'-(2''-methoxyethoxy)propyl-3-nitro-1,2,4-triazole I
, 1? (4,5 mmol) to 1,4-dioxane l
Add OmQ, drop 1.09 (6.2 mmol) of diethylaminosulfur trifluoride (DAST),
After the dropwise addition, the mixture was stirred and reacted at room temperature overnight. After the reaction, two liters of water were added to the solution to remove excess DAST, the solution was concentrated, and the concentrate was separated between chloroform and water. After washing the chloroform layer with water, it was dried over magnesium sulfate, filtered, the filtrate was concentrated, and the concentrate was isolated and purified by silica gel column chromatography to obtain the title 1-[2'-fluoro-3'-(2
”-methoxyethquine)propylco-3-nitro-1,
2°4-triazole 50071!9 was obtained.

'tlNMR (CDC123): δ-3,42(3
tl, s, -0Ctl, ), 3.49-3.92 (61
1, m, +13'mountain",llt"), 4.48 ~ 4,9
．． 0(2H,m,tlI')5.60(Ill,dm
, -Hz', J,,, -F=4511z),
8.42 (311°s, Hs) 19FNMR (CDC123XTFA standard): l13
．． 00ppm Production Example 39 \/ Fire Hs CCT(3 1,2-0-isopropylidene glycerol 6°09(
50 mmol)) and epichlorohydrin 18°59
(0.2 mmol) was dissolved in 50 ml of 1,4-dioxane, and 2.89 (50 mmol) of potassium hydroxide was dissolved in this.
) was added and reacted by heating at 70°C for 3 hours. After the reaction, 3-(2,
3-epoxypropyl)-1,2-0-isopropylidene glycerol, 6.99% was obtained.

2.3 g (11 mmol) of 3-(2,3-epoxypropyl)-1,2-0-isopropylidene glycerol and 1°89 of 3-nitro-1,2,4-triazole (
16 mmol) was dissolved in 1,4-dioxane 5i&,
The reaction was carried out by heating at 90°C for 3 hours. After the reaction, it is concentrated, the concentrate is separated into chloroform and water, the chloroform layer is dried over magnesium sulfate, and then filtered.1. , concentrate the filtrate, isolate and purify the concentrate by silica gel column chromatography,
1-(2°-hydroxy-4°-oxo-6',7'-
isopropylidene dioxyheptyl)-3-nitro-1
．． 1.59 of 2.4-triazole was obtained.

' HNMR (CDC123): δ = 1.38 (3
11,S, -C113), 1.42(311,s.

-CI+J, 3.40-3.83 (5H, m, H3°,
H6', -011).

3.70 (IH, dd, H7,, JH7, b=8H2,
J, +6. =6Hz).

4.80 (18, dd, Il7. b, JH7, a=
8Hz, Il, 6. = 711z).

4, 18-4.60 (4H, m,) 1. ',H,'
, +1. ), 8.39 (IH, s.

11,) 1-(2°-hydroquino-4°-oxo-6',7'-
Isopropylidene dioxyheptyl)-3-nide a-1
,2,4-triazolel,09(3,4mmol
) was added with 14-dioxane IOmQ, and 1°0 g of noethylaminosulfur trifluoride (DAST) (
After the dropwise addition, the mixture was stirred and reacted at room temperature overnight. After the reaction, water 2RI2 was added to the solution to remove excess DAST, and then the solution was concentrated.

The concentrate was separated between ethyl acetate and water, and the ethyl acetate layer was washed with water, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The concentrate was isolated and purified by silica gel column chromatography to obtain 1-(2"-fluoro-4°-oxo-6',
400 m9 of 7'-isopropylidenedioxyheptyl)-3-nitro-1,2,4-triazole was obtained.

'IINMR (CDCQ, s): δ-1, 32 (31
1,s, -CR2), 1,39(3H,s.

-C11,), 3.44-4.06 (6H, m,)13
', 85°, H7'), 4.08-4.40 (111
, i+, I(e'), 4.42-4.85 (21!,
m, Il,').

6.00 (illdm Ilt' Jl, F=48Hz
), 8.34 (ill, S, H5) I9FNMR (CD
CC3XTFA group #*): 113. Oppm Production Example Production T CHtCHFCH,0CH2CHCI-1ffiOI(
(65) H 1-(2°-fluoro-4°-oxo~6′.

7°-isopropylidene dioxyheptyl)-3=nitro-1,2,4-triazole 1.09 (3,4 mmo
Add 2N-1 (CQ, 50m12) to 1) and heat at 80℃ for 6
The mixture was heated and reacted for a period of time. After the reaction, 100 m of ethyl acetate was added, and after separation, the ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. After filtration,
The filtrate was concentrated, and the concentrate was isolated and purified by silica gel column chromatography to obtain 1-(2'-fluoro-4°-oxo-6°,7°-dihydroquinheptyl)-3-nitro-1.2.4 -Triazole 300s9 was obtained.

'HNMR (CDC5s) + 6 = 3.42~4
, 05 (81'l, m, Hs', H6'.

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R represents a fluorine-containing organic group. ] A 3-nitro-1,2,4-triazole derivative represented by the following. 2. In the formula, R is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, X is a hydrogen atom or a fluorine atom, Y is a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, or represents a hydroxyl group, or X and Y represent =O. Z is a hydrogen atom, a fluorine atom, a C_1 to C_5 alkyl group optionally substituted with a hydroxyl group, or a fluorine-containing alkyl group, formula: -(CHE)_m-CO-OR_
1 (Here, R_1 is a hydrogen atom, a C_1 to C_5 alkyl group or a fluorine-containing alkyl group, E is a hydrogen atom or a fluorine atom, and m is 0 or 1.) Formula: -CO-R_
2 (Here, R_2 is a C_1 to C_5 alkyl group or a fluorine-containing alkyl group.) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R_3 and R_4 are the same or different and are a hydrogen atom, a hydroxyl group, Or hydroxyl group, C_
It represents a C_1-C_5 alkyl group or a fluorine-containing alkyl group which may be substituted with a 1-C_5 alkoxy group or an amide group, or R_3 and R_4 form a 3- to 6-membered ring together with the nitrogen atom. E and m have the same meanings as above. ) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_3, R_4, E, m have the same meanings as above) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_3, R_4, E, m have the same meanings as above) Same meaning) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (R_3, R_4, E, m have the same meaning as above) Formula: -(C
HE)_mAR_5 (where A is an oxygen atom or a sulfur atom, R_5 is a hydrogen atom, or a C_1-C_5 alkyl group or a fluorine-containing alkyl group which may be substituted with a hydroxyl group, a C_1-C_5 alkoxyl group, or a C_1-C_5 oxyacyl group or -CO-R_6 (R_6 is a C_1 to C_5 alkyl group, or ▲ there is a mathematical formula, chemical formula, table, etc. ▼ (here R_7 is a C_1 to C_7 alkylene group, R_8
is a C_1-C_3 alkyl group. A has the same meaning as above. ). E and m have the same meanings as above. ) or formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (R_5 is a C_1 to C_5 alkyl group or fluorine-containing alkyl, E and m have the same meanings as above) Represents an atom or group. Furthermore, in Y and Z =CF-CF_3 or =CH
This includes the case where OR_6 is formed (R_6 is C_1 to C_
(5) fluorine-containing alkyl group). n represents an integer of 0 to 2. ] The 3-nitro-1,2,4-triazole derivative according to item 1, which is a fluorine-containing organic group represented by the following. 3. 3-nitro-1 according to item 2, wherein the group R has at least one fluorine atom on the carbon atom bonded to the nitrogen atom of the triazole ring or on the carbon atom bonded to the carbon atom
,2,4-triazole derivative. 4. Formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R represents a fluorine-containing organic group. ] A radiosensitizer containing a 3-nitro-1,2,4-triazole derivative as an active ingredient. 5. In the formula, R is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, X is a hydrogen atom or a fluorine atom, Y is a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, or represents a hydroxyl group, or X and Y represent =O. Z is a hydrogen atom, a fluorine atom, a C_1 to C_5 alkyl group optionally substituted with a hydroxyl group, or a fluorine-containing alkyl group, formula: -(CHE)_m-CO-OR_
1 (Here, R_1 is a hydrogen atom, a C_1 to C_5 alkyl group or a fluorine-containing alkyl group, E is a hydrogen atom or a fluorine atom, and m is 0 or 1.) Formula: -CO-R_
2 (Here, R_2 is a C_1 to C_5 alkyl group or a fluorine-containing alkyl group.) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R_3 and R_4 are the same or different and are a hydrogen atom, a hydroxyl group, Or hydroxyl group, C_
It represents a C_1-C_5 alkyl group or a fluorine-containing alkyl group which may be substituted with a 1-C_5 alkoxy group or an amide group, or R_3 and R_4 form a 3- to 6-membered ring together with the nitrogen atom. E and m have the same meanings as above. ) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_3, R_4, E, m have the same meanings as above) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_3, R_4, E, m have the same meanings as above) Same meaning) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (R_3, R_4, E, m have the same meaning as above) Formula: -(C
HE)_mAR_5 (where A is an oxygen atom or a sulfur atom, R_5 is a hydrogen atom, or a C_1-C_5 alkyl group or a fluorine-containing alkyl group which may be substituted with a hydroxyl group, a C_1-C_5 alkoxyl group, or a C_1-C_5 oxyacyl group or -CO-R_6 (R_6 is a C_1-C_5 alkyl group, or ▲ there is a mathematical formula, chemical formula, table, etc. ▼ (here R_7 is a C_1-C_7 alkylene group, R_6
is a C_1-C_3 alkyl group. A has the same meaning as above. ). E and m have the same meanings as above. ) or formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (R_5 is a C_1 to C_5 alkyl group or fluorine-containing alkyl, E and m have the same meanings as above) Represents an atom or group. Furthermore, in Y and Z =CF-CF_3 or =CH
This includes the case where OR_6 is formed (R_6 is C_1 to C_
(5) fluorine-containing alkyl group). n represents an integer of 0 to 2. ] The radiation sensitizer according to item 4, which is a fluorine-containing organic group represented by the following. 6. The radiation sensitizer according to item 5, wherein the group R has at least one fluorine atom on the carbon atom bonded to the nitrogen atom of the triazole ring or on the carbon atom bonded to the carbon atom.