JPH0759587B2 - Imidazolylphosphine compound and 1,2,4-triazolylphosphine compound - Google Patents

Description

The present invention relates to an intermediate compound for producing a diorganooxyorganothiophosphine compound useful as a stabilizer for an organic compound, and an intermediate compound for producing an oligodeoxynucleotide. The present invention relates to a raw material compound for producing a deoxynucleoside phosphoryl sulfide compound.

Conventional technology Diorganooxyorganothiophosphine compound [IV]
As shown in reaction formulas (1) and (2), a diorganooxychlorophosphine compound [I
There is a method of reacting I] with a thiol [III] or a method of reacting an organooxyorganothiochlorophosphine compound [VI] with an alcohol [VII].

(Wherein R ¹ and R ² have the same meanings as described below; R ³ represents an alkyl group or an aryl group, or R ³ OH
Represents a 5'-O, N-protected deoxynucleoside. ) (In the formula, R ¹ and R ² have the same meanings as described below; R ³ has the same meaning as described above.) Problems to be Solved by the Invention Using the above reactions (1) and (2), diorgano The advantage of producing oxyorganothiophosphine [IV] is that the starting materials diorganooxychlorophosphine compound [II], thiol [III], organooxyorganothiochlorophosphine compound [VI] and alcohol [VII] are used. ] Is easily available. However, in the reactions (1) and (2), a side reaction such as a disproportionation reaction may be induced along with the progress of the desired reactions (1) and (2), and therefore the compound [IV] and the by-product are generated. There are drawbacks such as the difficulty of separating the products and the yield of the compound [IV] is not so high.

Means for Solving Problems, Actions and Effects The present inventors, in view of the state of the art as described above, as a result of searching for a more general and high yield yielding compound [IV], The present invention was completed by finding that the imidazolylphosphine compound represented by the general formula [I] and the 1,2,4-triazolylphosphine compound serve as an intermediate compound for the production of the compound [IV].

(In the formula, R ¹ represents a lower alkyl group, an allyl group, a cyano (lower alkyl) group or a chlorophenyl group; R ² represents a lower alkyl group, a phenyl group, a tolyl group, a xylyl group or a chlorophenyl group; and X represents an imidazolyl group. Group or 1,2,4-triazolyl group.) Accordingly, the present invention relates to an intermediate compound [I] capable of providing an improved process for producing a diorganooxyorganothiophosphine compound [IV], In particular, when the compound is used for the above purpose, even in the reaction with a compound containing a functional group such as an amide group or keto group such as 5'-O, N-protected deoxynucleoside in the molecule, only the alcoholic hydroxyl group is selected. Of the compound [IV] in a high yield.

According to the present invention, the organic group R ¹ of the imidazolylphosphine compound represented by the general formula [I] and the 1,2,4-triazolylphosphine compound is basically an alcohol,
It is possible for the organic radical R ¹ of the compound to be considered as R ¹ OH. R ¹ is specifically a lower alkyl group, an allyl group, a cyano (lower alkyl) group or a chlorophenyl group.
The R ² is basically thiol is susceptible to organic radicals R ² of the compounds as contemplated as R ² SH, specifically, a lower alkyl group, a phenyl group, a tolyl group, a xylyl group or a chlorophenyl group Is.

Specific imidazolylphosphine compounds include methoxy-i-propylthioimidazolylphosphine, methoxy-t-butylthioimidazolylphosphine and methoxy-4-chlorophenylthioimidazolylphosphine, i.
-Propoxy-4-chlorophenylthioimidazolylphosphine, allyloxy-t-butylthioimidazolylphosphine, allyloxy-2-methylphenylthioimidazolylphosphine, β-cyanoethoxy-t-butylthioimidazolylphosphine, β-cyano Ethoxy-
There are 2-methylphenylthioimidazolylphosphine, 2-chlorophenyloxy-2-methylphenylthioimidazolylphosphine and the like. Examples of the 1,2,4-triazolylphosphine compound include methoxy-i-propylthio-1,2,4-triazolylphosphine and methoxy-t-butylthio-1,2,4-triazolylphosphine. In, methoxyphenylthio-1,2,4-triazolylphosphine, methoxy-2-methylphenylthio-1,2,4-triazolylphosphine, ethoxy-n-propylthio-1,2, 4-triazolylphosphine, i-propoxy-4-chlorophenylthio-1,2,4-triazolylphosphine, allyloxy-t-butylthio-1,2,4-triazolylphosphine, allyloxy- 2-methylphenylthio-1,2,4-
Triazolylphosphine, β-cyanoethoxy-t-butylthio-1,2,4-triazolylphosphine, β-cyanoethoxy-2-methylphenylthio-1,2,4-triazolylphosphine , 2-Chlorophenyloxy-2-methylphenylthio-1,2,4-triazolylphosphine, 2-
Chlorophenyloxy-2,6-dimethylphenylthio-
1,2,4-triazolylphosphine and the like can be mentioned.

According to the present invention, the azolylphosphine compound represented by the general formula [I] is a ligand exchange of a chlorophosphine compound [VI] and a trimethylsilylazole compound [VIII] as shown in the reaction formula (3). It can be easily produced by a reaction or a reaction of a bisazolylphosphine compound [X] and a thiol [III] [reaction formula (4)].

(In the formula, R ¹ , R ² and X have the same meanings as described above.) (In the formula, R ¹ , R ² and X have the same meanings as described above.) The reaction conditions and the like of the method for producing the compound [I] by the reaction (3) will be described. It progresses promptly, and such solvents include chloroform,
Mention may be made of methylene chloride, benzene, toluene and the like. Considering that the compound [I] is not so stable in water, it is preferable to use these organic solvents that have been distilled and purified after drying with a suitable desiccant before use. The molar ratio of compound [VI] to compound [VIII] may be in the range of 1: 1 to 5, but it is not a good idea to use it in a large excess considering the economical aspect, and the range of 1: 1 to 1.5 is preferred. used. It is desirable to carry out the reaction in the range of 0 ° C to 35 ° C. Further, the reaction time depends on the molar ratio of the compound [VI] and the compound [VIII], or the organic groups R ¹ and R ² of the compound [VI],
It is generally in the range of 5 to 30 minutes. But the reaction (3)
When carrying out, it is preferable to confirm the completion of the reaction by ¹ H NMR or the like.

The azolylphosphine compound [I] produced by the reaction (3) according to the present invention is not stable to heat and water so that it can be purified by distillation or chromatography, but according to the reaction (3), the compound [I] It is clear from the following two facts that I] is generated.

(1) After reacting the compound [VI] with the compound [VIII] under the above-mentioned reaction conditions, the organic solvent and the by-produced trimethylchlorosilane [IX] were distilled off under reduced pressure, and the ¹ H NMR spectrum of the obtained residue was obtained. Corresponds to the structure of compound [I].

(2) Dissolving the above residue in an organic solvent such as chloroform and adding an alcohol such as an equimolar amount of methanol such as alcoholysis to obtain a diorganooxyorganothiophosphine and an azole compound in a high yield [reaction Formula (5)].

(In the formula, R ¹ , R ² , R ³ and X have the same meanings as described above.) Thus, the compound [I] can be easily obtained by the reaction (3), but it is a raw material of the reaction (3). Chlorophosphine compound [VI] and trimethylsilylazole compound [VII
The compound [VI] can be produced by the method described in the literature, that is, the reaction (6) (GMKosolapoff et al., “Organic phosphorus C”).
ompounds ", vol.5, John Wiley & Sons (New York), 197
3 years and references cited).

(In the formula, R ¹ and R ² have the same meanings as described above; the base represents a base such as triethylamine and pyridine.) The trimethylsilylazole compound [VIII] is described in the literature (L. Birkofer et al., Chem. Ber., 93 , 2804 (1960)) [reaction formula (7)], but when X is either an imidazolyl group or a 1,2,4-triazolyl group, the compound is Since it is commercially available, it is convenient to use this.

(In the formula, X has the same meaning as described above.) Next, the case of producing the azolylphosphine [I] by the reaction (4) will be described. The reaction (4) smoothly proceeds in an organic solvent. Progressing, examples of such solvents include chloroform, methylene chloride, benzene, toluene and the like. As described above, these solvents should be purified by distillation after being dried with an appropriate desiccant before use. The molar ratio of compound [X] and compound [III] is preferably 1: 1 to 1.1. The reaction temperature is preferably in the range of 0 ° C to 35 ° C, and the reaction time varies depending on the kinds of the organic group R ¹ of the compound [X], the azolyl group X and the thiol [III], but is generally 30 minutes to 3 minutes.
It's time. However, when actually carrying out the reaction (4), it is better to confirm the completion of the reaction by ¹ H NMR or the like.

The azolylphosphine compound [I] produced by the reaction (4) cannot be isolated and purified by distillation, chromatography or the like as described above, but when the above reaction conditions are used, the compound [I] almost disappears. Obtained purely and quantitatively is shown by ¹ H NMR spectrum and alcoholysis of the reaction. Therefore, the reaction solution thus obtained can be used as it is for the next reaction or the like in so-called in situ.

Now be described reaction (4) of the raw material bis azolyl phosphine compound is the [X], the compound [X] is literature (e.g., J.Fourrey et, Tetrahedron Lett., 25, 4
511 (1984)),
That is, it can be produced by the reaction (8).

(In the formula, R ¹ and X have the same meanings as described above.) Regarding which of the reaction (3) and the reaction (4) is used as the method for producing the azolylphosphine compound represented by the general formula [I], Although not limited, it is generally determined by the availability of the starting compounds [VI] and [X].

Thus, the azolyl phosphine compound [I] obtained by the reaction (3) or the reaction (4) is reacted with an alcohol to produce a diorganooxyorganothiophosphine [IV].
However, it also reacts with 5'-O, N-protected deoxynucleosides to give deoxynucleoside phosphoryl sulfide compounds which are intermediates for the production of oligodeoxynucleotides in good yield. For example, 5'-O-dimethoxytritylthymidine and methoxy-2-methylphenylthio-1,2,
4-triazolylphosphine was reacted in chloroform to give 5'-O-dimethoxytritylthymidine-3 '.
-(Methoxy-2-methylphenylthio) phosphine is obtained in good yield.

The abbreviations used in this specification have the following meanings.

Me: methyl group, Et: ethyl group, n-pr: n-propyl group, i-pr:
i-Propyl group, n-Bu: n-butyl group.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to Examples.
The invention is not limited to the examples.

Example 1 Ethoxy-n-propylthiochlorophosphine [VI]
To a solution of (0.933g, 5mmol) in toluene (30ml),
And trimethylsilyl-1,2,4-triazole [VIII]
A solution of (0.706 g, 5 mmol) in toluene (20 ml) was added at 0 ° C. It was stirred at that temperature for 10 minutes and the low boiling fraction was trapped under reduced pressure at -78 °. The trapped fraction was fractionally distilled to obtain trimethylchlorosilane [IX] (bp 57 ° C / 760mmH
g, ¹ HNMR (CDCl ₃ , TMS) δ; 0.43 (s, (C H ₃ ) ₃ SiCl)) 0.4
67 g (86%) was obtained. The ¹ H NMR spectrum of the residue was consistent with the structure of ethoxy-n-propylthio-1,2,4-triazolylphosphine [I], and the yield was 1.03 g (ethoxy-n
-Propylthio-1,2,4-triazolylphosphine [I], the yield was 94%). ¹ HNMR (C
DCl ₃ , TMS) δ; 1.02 (t, J = 7.0Hz, 3H, C H ₃ CH ₂ CH ₂ S-),
1.18 (t, J = 7.0Hz, 3H, C H 3 CH 2 O -), 1.55-1.95 (m, 2H,
C H ₃ CH ₂ CH ₂ S-), 1.50-3.05 (m, 2H, CH ₃ C H ₂ CH ₂ S-),
_{3.50-4.35 (m, 2H, CH 3} C H 2 O -), 8.05 (s, 1H, 1,2,4- triazolyl group 3-position), 8.44 (s, 1H, 1.2,4- triazolyl group 5-position) ppm. After that, chloroform (30m
l) and n-hexane (20 ml) were added, ethanol [VII] (0.27 ml, 4.7 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 10 minutes. After separating the produced white crystals, the liquid was concentrated and the residue was distilled to obtain a fraction with a boiling point of 83-84 ° C / 7mmHg of 0.
839 g were obtained. This was in agreement with the diethoxy-n-propylthiophosphine [IV] synthesized separately by a known method in its boiling point and ¹ H NMR spectrum. Yield 91%. ¹ HNMR (CDCl ₃ ,, TMS) δ; 0.98 (t, J = 7.0Hz, 3H, C H ₃ CH ₂ CH ₂
S -), 1.28 (t, J = 7.0Hz, 6H, 2 × C H 3 CH 2 O -), 1.40-
_{1.90 (m, 2H, CH 3} C H 2 CH 2 S -), 2.40-2.90 (m, 2H, CH 3 CH 2
C H ₂ S-), 3.50-4.30 (m, 4H, 2 x CH ₃ C H ₂ O-) ppm. The melting point and ¹ H NMR spectrum of white crystals were 1H-1,2,4
-In agreement with that of the triazole. mp119-120 ° C, ¹ H
NMR ((CD ₃ ) ₂ SO, TMS) δ; 8.26 (s, 2H, 3 and 5 positions),
13.5 (s, 1H, 1st place) ppm.

Examples 2 to 5 The same operations as in Example 1 were carried out using the raw material compounds shown in Table 1 below, and the azolylphosphine compound [I] and diorganooxyorganothiophosphine compound [IV] shown in Table 1 were used. ] Respectively.

Example 6 2-Propenyloxybis (1,2,4-synthesized from 2-propenyloxydichlorophosphine [XII] and trimethylsilyl-1,2,4-triazole [VIII] by a known method.
Triazolyl) phosphine [X] (1.121 g, 5 mmol)
O-Toluenethiol [III] (0.621 g, 5 mmol) was added to a chloroform (25 ml) solution of the above at 0 ° C. After stirring at room temperature for 2 hours, the solution was allowed to stand at 0 ° C. for 30 minutes. White crystals of the resulting IH-1,2,4-triazole [XI] (0.321 g, 93% ^{yield) mp119-120 ℃, 1 HNMR ((} CD 3) 2 SO, TMS) δ; 8.
After separating 26 (s, 2H, 3rd and 5th), 13.5 (s, 1H, 1st) ppm, the solution was concentrated under reduced pressure to obtain ¹ HNM of the obtained residue.
The R spectrum was consistent with the structure of 2-propenyloxy-2-methylphenylthio-1,2,4-triazolylphosphinated [I]. _{^{1 HNMR (CDCl 3, TMS)}} δ; 2.43 (s, 3H, o-C H 3 C 6 H 4 S -), 4.3
0−4.95 (m, 2H, CH ₂ = CH−C H ₂ O−), 5.05−5.45 (m, 2H, C H
_{2 = CH-CH 2 O -} ), 5.60-6.05 (m, 1H, CH 2 = C H -CH 2 O
-), 6.95-7.55 (m, 4H , o-CH 3 C 6 H 4 S -), 8.18 (s, 1H, 1,
2,4-triazolyl group 3rd position), 8.46 (s, 1H, 1,2,4-triazolyl group 5th position) ppm. Yield 1.33 g, 95% yield (as 2-propenyloxy-2-methylphenylthio-1,2,4-triazolylphosphine [I]).

Then, chloroform (30 ml) and n-hexane (20 ml) were added to the above residue, and methanol [VII] (0.19 ml, 4.
75 mmol) was added. After stirring at room temperature for 10 minutes, white crystals of 1H-1,2,4-triazole [XI] produced (4.5
1g, yield 95%) mp119-120 ° C, ¹ HNMR ((CD ₃ ) ₂ SO, TM
S) δ; 8.26 (s, 2H, 3rd and 5th), 13.5 (s, 1H, 1st) p
After removing pm, the liquid was distilled to obtain 1.05 g of a fraction of 103-105 ° C./0.4 mmHg. This is a separately synthesized methoxy-2-
The boiling point and ¹ H NMR spectrum of propenyloxy-2-methylphenylthiophosphine [IV] were in agreement. Yield 9
1% ¹ H NMR (CDCl ₃ , TMS) δ; 2.42 (s, 3H, oC H ₃ C ₆ H ₄ S-), 3.
64 (d, J = 10.0Hz, 3H, C H 3 O -), 4.10-4.65 (m, 2H, CH 2
_{= CH-C H 2 O -} ), 5.00-5.40 (m, 2H, C H 2 = CH-CH 2 O-),
_{5.60-6.10 (m, 1H, CH 2} = C H -CH 2 O -), 6.80-7.55 (m, 4
H, o-CH ₃ C ₆ H ₄ S-) ppm.

Example 7 β-cyanoethoxy bis (1,2,4) synthesized from β-cyanoethoxydichlorophosphine [XII] and trimethylsilyl-1,2,4-triazole [VIII] by a known method.
Example 6 from 4-triazolyl) phosphine [X] (1.186 g, 5 mmol) and o-toluenethiol [III]
1H-1,2,4-triazole [XI]
(0.314 g, 91% yield) and β-cyanoethoxy-2-methylphenylthio-1,2,4-triazolylphosphine [I] (1.39 g, 95% yield) ¹ HNMR ((CDCl ₃ , TMS) δ; 2.45 (s, 3H, oC H ₃ C ₆ H ₄ S-),
2.64 (t, J = 6.0Hz, 2H, NCC H ₂ CH ₂ O-), 3.90-4.75 (m, 2
H, NCCH ₂ C H ₂ O-), 6.90-7.60 (m, 4H, o-CH ₃ C ₆ H ₄ S-), 8.
18 (s, 1H, 1,2,4-triazolyl group 3rd position), 8.48 (s, 1H, 1,
2,4-triazolyl group 5 position) ppm. Respectively obtained. Then β-cyanoethoxy-2-methylphenylthio-1,
2,4-Triazolylphosphine [I] and i-propanol [VII] (0.364 ml, 4.75 mmol) were reacted in the same manner as in Example 6 to give 1H-1,2,4-triazole [XI] ( 0.315
g, 96% yield) and β-cyanoethoxy-i-propoxy-
2-Methylphenylthiophosphine [IV] (1.211 g, yield 90%, bp 145-147 ° C / 0.5 mmHg, ¹ HNMR (CDCl ₃ , TMS)
δ; 1.30 (d, J = 6.0 Hz, 3H, 0.5 × (C H 3) 2 CHO -), 1.32
(D, J = 6.0Hz, 3H , 0.5 × (C H 3) 2 CHO -), 2.43 (s, 3H, o-
C H ₃ C ₆ H ₄ S-), 2.65 (t, J = 6.0Hz, 2H, NCC H ₂ CH ₂ O-), 3.8
5-4.60 (m, 3H, Me ₂ C H O- and NCCH ₂ C H ₂ O-), 6.85-
7.55 (m, 4H, o- CH 3 C 6 H 4 S-) ppm) were respectively obtained.

Examples 8 to 10 As chlorophosphine compound [VI], methoxy-2-
Methylphenylthiochlorophosphine (Example 8), 2-
Chlorophenyloxy-2,6-dimethylphenylthiochlorophosphine (Example 9) or isopropoxy-4
-Chlorophenylthiochlorophosphine (Example 10) was used and in Example 10 the silylazole compound (VII
The method of Example 1 was repeated except that trimethylsilylimidazole was used as I) to obtain an azolylphosphine compound [I] as shown in Table 2.

Claims (1)

[Claims] 1. An imidazolylphosphine compound and a 1,2,4-triazolylphosphine compound represented by the general formula [I]. (In the formula, R ¹ represents a lower alkyl group, an allyl group, a cyano (lower alkyl) group or a chlorophenyl group; R ² represents a lower alkyl group, a phenyl group, a tolyl group, a xylyl group or a chlorophenyl group; and X represents an imidazolyl group. Group or 1,2,4-triazolyl group.)