JPS5989675A - Phthalidyl ammonium derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (X is halogen, trihalogenoacetyloxy, alkylsulfonyloxy or arylsulfonyloxy; R<1>-R<3> are alkyl, or R<1> is alkyl and R<2> and R<3> form a 5-6-membered ring which may contain N together with O or a group of formula II represents quinuclidine; R<4> and R<5> are H, trialkylsilyloxy, alkoxyl, NO2, CN, COOH or alkoxycarbonyl). EXAMPLE:N,N,N-Triethyl-3-oxo-1,3-dihydro-1-isobenzofuranyl ammonium bromide. USE:A raw material for an antitumor agent 1-phthalidyl-5-fluororacil derivative. PROCESS:A compound of formula II is reacted with a tertiary base of formula IIIin an aprotic solvent, e.g. benzene, tetraydrofuran (THF) of dimethylformamide (DMF), at room temperature or under heating to afford the aimed compound of formula I .

Description

[Detailed Description of the Invention] More specifically, it relates to a phthalidyl ammonium derivative represented by the following general formula (I).

(In the formula, X is halogen, trihalogenoacetyloxy, alkylsulfonyloxy.

mataha arylsulfonyloxy Expression.

Do B/, R2, and Bi each represent alkyl? B/ is alkyl, and R3 may contain oxygen together with the adjacent nitrogen atom! Or the member ring is represented by p/ \R3 which represents gin.

(R'' and R' each represent hydrogen, trialkylsilyloxy, alkoxy, nitro, cyano, carboxy, or alkoxycarbonyl) The phthalidyl ammonium derivative provided by the present invention is l-phthalidyl represented by the general formula (II). - It can be used as a raw material in the production of j-fluorouracil derivatives.

(In the formula, R'' and R'' have the same meanings as defined above.) The l-phthalidyl-!-fluorouracil derivative obtained using the compound of the present invention has an excellent antitumor effect, particularly for uterine cancer, esophageal cancer, etc. Cancer, skin cancer.

Stomach cancer, lung cancer, liver cancer, colorectal cancer, pancreatic cancer, breast cancer.

It is a useful compound that is effective in the treatment and prevention of metastasis of malignant tumors such as bladder cancer, chorionic tumor, brain tumor, lymphosarcoma, and leukemia. [Tokukai Akira! ;7-IAIf/.

Tokukai Akira! There is a description of this in 7-Otsu 737 Za etc. ] The present inventors have completed the present invention as a result of intensive research aimed at improving the manufacturing method of l-phthalidyl-j-fluorouracil derivatives.

In the above definition, halogen means fluoro, chloro, bromo, and iodo, and trihalogenoacetyloxy means trifluoroacetyloxy, trichloroacetyloxy, tribromoacetyloxy, etc. Alkylsulfonyloxy is an alkylsulfonyloxy having a carbon number lNj, for example, methylsulfonyloxy,
Ethylsulfonyloxy, propylsulfonyloxy.

Isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, t-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, t-
Examples include pentylsulfonyloxy. Arylsulfonyloxy means benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, p-chlorobenzenesulfonyloxy, p-methoxybenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, and the like. Alkyl is an alkyl having carbon number/-5, such as methyl, ethyl, propyl,
Isopropyl, butyl.

These are isobutyl, pentyl, and isopentyl. The j- or t-membered ring which may contain oxygen together with adjacent nitrogen atoms means pyrrolidino, piperidino, morpholino, and the like. Trialkylsilyloxy is silyloxy having three alkyl groups having the same or different carbon atoms of 1 to 1. Trimethylsilyloxy, triethylsilyloxy, tripropylsilyloxy, dimethylethylsilyloxy.

Dimethylpropylsilyloxy, diethylmethylsilyloxy, methylethylpropylsilyloxy, dimethylbutylsilyloxy, dimethyl-butylsilyloxy, etc. are meant. Alkoxy is an alkoxy having carbon number/−,1, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-
Butoxy.

These include pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, and the like. Alkoxycarbonyl is alkoxycarbonyl having the alkoxy group described above.

Compound (1) of the present invention can be easily produced by reacting a compound represented by the following general formula (m) with a tertiary base represented by the general formula (M).

(Space below) (In the formula, x, R', R', R3, R'', and v have the same meanings as above.) As the tertiary base represented by the general formula (PJ), trimethylamine, triethylamine, trimethylamine, etc. lopropylamine, tri-n-butylamine, N-methylpyrrolidine, N
Examples include -ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, and quinuclidine. Further, the compound represented by the general formula (I[I) is a commercially available product or can be easily produced by a known method described in literature. [
For example, JP-A-37-/Otsuzaf/] The above reaction is carried out in a suitable solvent at room temperature or under heating, and takes several hours to several days to complete the reaction.

Solvents are dichloromethane, benzene, acetonitrile,
The solvent may be appropriately selected from aprotic solvents such as tetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. In addition, these reactions can be carried out using appropriate sodium halides, potassium halides,
Alternatively, it may be promoted by adding a catalytic amount of tetraalkylammonium halide.

Compounds of the invention also include. From a compound in which X represents halogen in general formula (I), X is trihalogenoacetyloxy by reaction with the corresponding silver salt.

It can be converted to a compound representing alkylsulfonyloxy or arylsulfonyloxy. The reaction is carried out in an appropriate solvent at room temperature and requires several hours to several days to complete one reaction. What is the solvent?

The solvent may be appropriately selected from aprotic solvents such as acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc., but acetonitrile is preferably used.

In order to produce l-phthalidyl-j-fluorouracil derivatives using the compound of the present invention, one compound of the present invention and 3-fluorouracil C (hereinafter abbreviated as 3-FU) are mixed in an appropriate solvent in the presence of a base. are reacted at room temperature. The reaction is complete in a few hours.

Solvents are acetonitrile and tetrahydrofuran.

Dimethylformamide, dimethylacetamide.

Although the solvent may be appropriately selected from aprotic solvents such as dimethyl sulfoxide, it is preferable to use dimethyl formamide or dimethyl sulfoxide. As the base, triethylamine, tri-n-butylamine, diisopropylethylamine.

Pyridine, dimethylaminopyridine, picoline.

Organic bases such as collidine, dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate may be used, but triethylamine is preferably used.

The above method using the compound of the present invention as a raw material,
JP-A-Sho using 3-halogenophthalide as a raw material! ;7-/Otsu 1#/ is advantageous in that the above method allows N (1)-substituted-3-FU to be obtained selectively and in good yield.

The by-product of N(1), N(3)-disubstituted-,5-FU is hardly observed.

The compound of the present invention is methanpicillin (t
It can also be used as a raw material for (alampicillin).

Examples and reference examples are shown below to clarify one aspect of the present invention.

Example 1 Production of rum 2 3-Bromo-43-dihydro-1-isobenzofuranone 113211 (&θ mmol) and triethylamine 2
7t7wl (2θθ mmol) and tetrahydrofuran♂! The reaction was carried out in iml at room temperature for 96 hours, and the precipitated crystals were filtered and washed with dichloromethane to obtain the title compound 2.
110111/ (yield) is obtained.

Melting point 173~/711'C NMR: δd, DM80 723; (t, J=lOH1
, 9H).

3,! ;f (q, J=JQHz, OtoH), 71
g (s, IH), 7♂θ~Ir, 23 (m, gH) Elemental analysis (as C,, H2oNo, Br): Calculated values: c, t, io/:H, 6, II2:N , Hiroq6 experimental value: c, 33. θ7; H1, l; N, ← Example column production P 3-bromo-/, 3-dihydro-noisobenzofuranone/13g1 (2jE rimole) and N-methylmorpholine 2.76ml (2jE rimole) were reacted in 20 ml of benzene at room temperature for 700 hours, and the precipitated crystals were filtered and washed with benzene to give the title compound 36. j2f (yield r3
h).

Melting point 19g~2θo'c NMR: δdtDMSO3,03(s, 3H),
3. II-II2 (m.

IH), 733 (8, IH), 7J”13 (m, 1AH
) Example 3 Production of Rum I Sodium iodide, 223IIv (lj'i, rimole) is reacted in 20 ml of acetonitrile by heating under reflux and stirring for 7 hours. After distilling off the solvent and excess triethylamine under reduced pressure, dichloromethane is added to the residue and the precipitated crystals are poured into the furnace to obtain crude crystals of the title compound j.

NMR: δdGDMSO7217 (t, J=/l, jH
z, 9H).

3,! ;9(q, J=IJHz, /;H),'Z23
(s, IH), 77θ~za27 (m, 'JH) Example 1 Production of l-methyl-q-(3-oxo-43-dium chloride) get.

NMR: δd, DMSO3θ3(s, JH), 3
．． 7-11.2 (m.

♂H), 7u3 (s, /H), 2 to 79~! ;(m,
1lH).

Example j-1 Production of autotrifluoroacetate Bromide/N,N,N-)diethyl-3-oxo/,3-
Dihydro-7-isobenzofuranylammonium 21A
θI (/2.7 mmol) and silver trifluoroacetate QJl
f (12.7 mmol) in acetonitrile at room temperature for 63 hours, the solvent was distilled off under reduced pressure, dichloromethane was added to the resulting residue, and silver bromide was removed by filtration to obtain the P solution. is concentrated under reduced pressure to obtain the title compound 7.

NMR: δd, DMSOt23(i, , r-, θ
Hz, 9H).

3, jl, (q, J-JθI(z, Otsu H), 707(s
, /H), '7♂θ~za27 (m, tAH).

(Left below) 16- Bromide/N,N,N-)diethyl-3-oxo/, 3-
Dihydro-7-isobenzofuranylammonium22.
131 cl, 7 r mmol) and silver methanesulfonate 1
3tf in acetonitrile for 1 hour.Then, the solvent was distilled off under reduced pressure, dichloromethane was added to the resulting residue, and silver bromide was removed by filtration.The resulting filtrate was concentrated under reduced pressure to obtain the title compound. get l.

NMR: δd4DMSO723(t, J=lr, QHl
, 9H), Q30 (s 1.?H), 3Jj (q, J=
lOHz, ,<H), 7θ3(S.

/H),7za0-,lj(m,4!)I).

Example 7 N,N,N-triethyl-3-oxo-43-dihydrobromide/N,N,N-)diethyl-3-oxo-43-dihydro-l-isobenzofuranylammonium 21za7
g (9j mmol) and silver p-toluenesulfonate (!;, 9!;E mmol) in triacetonitrile.
The reaction mixture was allowed to react for 9 hours, and then the solvent was distilled off under reduced pressure. Dichloromethane was added to the resulting residue and the silver bromide was removed by filtration, and the resulting P solution was concentrated under reduced pressure to obtain the title compound.

NMR: δd4DMS0/22c t, J4QHz
, 9H).

227 (s, 3H), 3! ;3(q, J-1, θHz,
1. H), 700 (s, /H), 7#) (d, J- and θ
Hz, 2H), 73θ (d.

J-f, θHz, 2H), Zza0 px3cm, ttH
).

Example Preparation of Zaramr 19-3-bromo-43-dihydro-1-isobenzofuranone/2. /311 (1029 mol) and 127xl (1029 mol) of N-ethylmorpholine are dissolved in 2/ml acetonitrile and reacted under heating under reflux for 3 hours.

When the crystals that precipitate after cooling are removed from the furnace and washed with ether, 2.
31. The title compound 10 is obtained in fl (yield: 72 cm).

Melting point /13~lt♂°C NMR: δdtDMS0121 (t, J=7Hz
, JT(), 3. ! ; ~442 (m, lθH)
, 730 (s, /H), 7f3-130 (m.

tH) Reference Example 1 20 - Compound obtained in Example 1 23.1ltfl (1029
The title compound/12J41 (yield 9
3tI)) is obtained. This was recrystallized from dimethyl sulfoxide-water to obtain white crystals with a melting point of 29θ°C or higher.

Elemental analysis (as C72H70□N, 2F): Calculated value:
C, j'4<97. H 1,1.9; N, 10 Otsu 9;
F, 7.2g experimental value: C,! ;'A93;,H,2,77,N,/
θ3f; F, 7 ot q U
), Mu11. (10, θOO).

ax NMR: δ' ADMSO1/l, 31. (broa
d, /H), 7J~ni 2(m, &H), 7j Otsu(
s, /H), 7 Otsu 7 (cl, J=7Hz.

/H).

Saiko week 2 (below the margins) //, t-FU3. Example with g♂g (26.7 mmol)!
Compound 3f, ItθI (26,7 E') mol) obtained in , and anhydrous potassium carbonate 3.1.911 (26,7 mmol) were mixed with dimethyl sulfoxide 3,! ml and stir well at room temperature for tS hours to react. The reaction solution was poured into about 300 ml of ice water containing 27 tsl of normalized hydrochloric acid, and the mixture was heated for about 13 tsl.
After stirring for a minute, the precipitated crystals were separated and mixed with 30 kg of water 3 times, once with 30 txt of methanol, and 30 tx ether.
After washing once with l and drying, the title compound //1,. 3;1
．． f (yield 9'Ao) obtained.

Reference Example 3 -2 - 3-FU9271f (7/3 mmol) and 7 molar equivalents of the compound obtained in Example J were dissolved in anhydrous dimethyl sulfoxide Awl, and triethylamine θ! ; tel
After adding (3.6 mmol) and reacting at room temperature for 1 hour, the reaction solution was poured into ice water containing 2N hydrochloric acid and stirred for 30 minutes. By counting the precipitated crystals, 1/7719 of the title compound (yield 9g4) is obtained.

Reference example (blank below) Compound 6 was mixed with j-FU in dimethyl sulfoxide, and 7
When the reaction is carried out at room temperature in the presence of a molar equivalent of anhydrous potassium carbonate, the title compound 1/ is obtained in good yield.

Reference example! (Left below) Example! j-F without purification of compound 7 obtained in
U/:6. l (/2.7 mmol) in 32 ml of anhydrous dimethylformamide, and triethylamine θ/
After adding 1 ml (127 lmol) and reacting at room temperature for 1 hour, the reaction solution was poured into 320 g of ice water containing 7 ml of 2N hydrochloric acid.
ml and stir for 30 minutes.

27- By counting the number of precipitated crystals, the title compound/13,
/4 fl (yield 9-) is obtained.

Reference example Otsu 21- <! -FUO♂za/lIC6.71rmmol) was dissolved in anhydrous dimethylformamide/6txl, and 91AIJl of triethylamine (OA 7J"i, rimole) was added and reacted at room temperature for 13 hours. The reaction solution was diluted with 2N hydrochloric acid 'Awl The mixture is poured into 10 ml of ice water containing IAO and stirred for 30 minutes. The precipitated crystals are collected by filtration to obtain the title compound //Itzag (yield: 9j).

Reference Example 7 (blank below) Compound 9 obtained in Example 7 was purified by j-F.
UO77'tfl (more than 129 mol) was dissolved in anhydrous dimethylformamide 141w1, and triethylamine (t3plcθtOj mol) was added and reacted at room temperature for 73 hours. The two reaction solutions were diluted with ice water containing 3 ml of 2N hydrochloric acid/gθ.
ml and stir for 30 minutes.

By counting the number of precipitated crystals, the title compound/11,
(yield: 96 cm).

Reference example! υ 0 l compound 10 in dimethyl sulfoxide with j-FU,
When reacted at room temperature in the presence of 1 molar equivalent of anhydrous potassium carbonate, the title compound 1/ is obtained in good yield.

Patent applicant: Shionogi & Co., Ltd. 859-

Claims (1)

[Claims] General formula: (wherein, X is halogen, trihalogenoacetyloxy,
Represents alkylsulfonyloxy and arylsulfonyloxy. Do R', R', and HJ each represent alkyl? HJ is alkyl, and 1 and HJ represent j or a 6-membered ring which may contain oxygen together with the adjacent nitrogen atom. death. f and R'' each represent hydrogen, trialkylsilyloxy, alkoxy, nitro, cyano, carboxy, or alkoxycarbonyl.