JPS59110681A - Preparation of thiolcarbonate of 2-mercaptopyrimidines - Google Patents

Abstract

PURPOSE:In preparing the titled compound by reacting a corresponding thiol chloroformate with a corresponding alcohol in the presence of an organic base, to carry out purification in a short time advantageously, by bringing the prepared desired compound into contact with an aliphatic primary alcohol. CONSTITUTION:In preparing a compound shown by the formula II (R<3> is benzyl or alkyl which may containing a protecting group) useful as an amino group- protecting agent, etc. useful in syntheses of peptide or preparation of antibiotic by reacting a compound shown by the formula I (R<1> and R<2> are H, or alkyl) with benzyl alcohol which may contain a substituent group or an aliphatic secondary-tertiary alcohol, the prepared desired compound is brought into contact with 1-10C, preferably 1-5C aliphatic primary alcohol, especially methanol or ethanol, so that a bis derivative shown by the formula III as a by-product contained in the desired compound is removed advantageously in a short treatment time with suppressing decomposition of the desired compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing thiol carbonate of 2-mercaptopyrimidines (hereinafter simply referred to as thiol carbonate).

For example, t-butyluda, 6-dimethylpyrimidyl-corchiol carbonate, benzyl-tei, 6-dimethylpyrimidyl-thiol carbonate, p-methoxybenzyruta, 6-dimethylpyrimidyl-corchiol carbonate, etc. Thiol carbonate is useful as an amine group protecting agent used during peptide synthesis or the production of antibiotics.

As a method for producing thiol carbonate, for example, Tokkosho! As described in No. f/-3390, 1 the following general formula (
The following general formula (1 ) (In the formula, R1 and R3 have the same meaning as the general formula for the front legs)
Thiol chloroformate of 1-mercaptopyrimidines represented by (hereinafter simply referred to as thiol chloroformate), for example, benzyl alcohol which may have a substituent or aliphatic aliphatic or tertiary alcohol. 9, the following general formula [wherein R' and R1a have the same meaning as the preceding general formula,
A method for producing a thiol carbonate represented by R3 represents a benzyl group or an alkyl group which may have a substituent is known.

However, in this method, a part of the thiol chloroformate represented by the forepaw general formula [I] produced during the production of thiol chloroformate is used as a starting material for the forepaw general formula (ill). It reacts with the alkali metal salts of rhinocerospyrimidines, and since the generated thiol chloroformate itself is thermally unstable, a portion of it tends to undergo a condensation reaction. Therefore, in the thiol carbonate finally obtained, the following general formula (fV) (in the formula, R1 and R3 have the same meaning as the front leg general formula) generated by these side reactions is included.
s, s'-disubstituted dithiocarbonate of pyrimidinethiols represented by (hereinafter simply referred to as bis-byproduct)
This results in the inclusion of Since bis-byproducts have similar properties to thiol carbonate, it is difficult to remove bis-byproducts contained in thiol carbonate.

The applicant previously proposed a method of contacting the thiol carbonate obtained by the reaction with water in the presence of a hydrohalide salt of an organic base as a method for removing bis-byproducts in thiol carbonate. did. (Unexamined Japanese Patent Publication Show 1g-1
17873) However, although this method is excellent as a method for purifying thiol carbonate, the treatment time may be long depending on the type of thiol carbonate, and if heating is performed to shorten the treatment time, thiol Carbonate decomposition also tends to occur.

In view of the above circumstances, the present inventors investigated an improved method for purifying thiol carbonate that suppresses the decomposition of thiol carbonate and requires a shorter processing time.
The present invention was completed based on the knowledge that the object of the present invention can be achieved by bringing the thiol carbonate obtained through the reaction into contact with a specific compound.

That is, the gist of the present invention is to convert a thiol chloroformate of λ-mercaptopyrimidine represented by the general formula CD into a benzyl alcohol which may have a substituent or an aliphatic secondary or In a method for producing a thiol carbonate of Komelkabutopyrimidine represented by the general formula [,1]] by reacting it with a tertiary alcohol, the obtained thiol carbonate is brought into contact with an aliphatic 7th-grade alcohol. The present invention relates to a method for producing thiol carbonate of comelkabutovirimidines, which is characterized in that the thiol carbonate is processed.

The present invention will be explained in detail below.

The thiol chloroformate targeted by the present invention is a compound represented by the general formula [1], and usually,
Dau-6-dimethylpyrimidyl-λ-thiol chloroformate), 4Z, A-diethylpyrimidyl-thiol chloroformate, Tei-methylpyrimidyl-1-thiol chloroformate, termethyl-6-nitylpyrimidyl-chloroformate All chloroformate, pyrimidyl-2-
Examples include thiol chloroformate. In addition, when R1 or R2 in the front leg general formula (1) is an alkyl group, an alkyl group having a carbon number of /~S is preferable.

On the other hand, examples of the benzyl alcohol, aliphatic secondary alcohol, or tertiary alcohol that may have a substituent include benzyl alcohol; P-methoxybenzyl alcohol, P-ethoxybenzyl alcohol, P- Benzyl alcohol having a substituent such as a lower alkoxy group, a halogen atom, or a nitro group with a carbon number/~j such as chlorobenzyl alcohol and P-nitrobenzyl alcohol; a carbon number of 3 or more such as θθC-butyl alcohol and esc-amyl alcohol /, 2 aliphatic secondary alcohol i Examples include aliphatic tertiary alcohols having 3 to 7.2 carbon atoms such as tert-butyl alcohol and tart-amyl alcohol. The reaction is carried out in the presence of an organic base, which is usually pyridine, quinoline, triethylamine, N,
Tertiary amines such as N-diethylaniline are used. The amount of organic base to be used is usually 0.3 to /θ mole times, preferably 7 to 7.3 times the amount of thiol chloroformate.
It is twice as many moles.

Although the reaction of the present invention can be carried out in the absence of a solvent, it is preferably carried out in the presence of a solvent.

Examples of solvents used in the present invention include pentane,
aliphatic hydrocarbons such as hexane, heptane, octane,
Inert organic solvents such as aromatic hydrocarbons such as benzene, toluene, and chlorobenzene, chloro, 1 (such as lum, carbon tetrachloride, and methylene chloride), and roghenich hydrocarbons, and ethers such as diisopropyl ether Rudel and diethyl ether are used. Particularly preferred are water-insoluble organic solvents such as hydrocarbons or chlorofluorinated water. These inert solvents can be used alone or in combination. In this case, the amount of solvent used is usually 0.00% relative to the chloroformate. , 1-10 times the weight.

The reaction temperature usually falls between -lθ and goC, and if it is too low, the reaction rate will be slow, and if it is too high, on the other hand, a large amount of by-products will be produced, which is not preferable.

In addition, the reaction time is usually -~2'1 at the above temperature.
It's time. In the reaction of the present invention, since chloroformate easily reacts with water, it is usually preferable to carry out the reaction while keeping the moisture content in the reaction system as low as possible. Although it is an essential requirement that the thiol carbonate of the general formula [...] be brought into contact with an aliphatic primary alcohol, the reaction mixture may be treated as it is or the reaction mixture may be treated at the point of contact treatment. This may be done after the thiol carbonate is once separated. In addition, when carrying out a contact treatment after separating the thiol carbonate, it is usually preferable to dissolve the thiol carbonate in the inert solvent used in the above-mentioned reaction.

The aliphatic primary alcohol usually includes methanol,
Ethanol, n-propanal, n-butanol, n-
Number of carbon atoms such as octatool) /~10 preferably /
~j aliphatic primary alcohols, among which,
Particular preference is given to methanol or ethanol. The amount of these alcohols used is usually 0.0% relative to the thiol carbonate. 1 to 10 times the mole, preferably 0.2 to 10 times the mole.If this amount is too small, the general formula (IV
) can not be removed sufficiently, and even if there is a large amount, the effect remains the same and it is not economical.

The temperature of the contact treatment with the aliphatic 7th-grade alcohol varies somewhat depending on the type of thiol carbonate, but is usually -10
-40°C, preferably 0 to 30°C; if this temperature is too low, the decomposition rate of bis-byproducts is slow and the processing time becomes longer; This is not preferable because the parts may disintegrate. Also, the processing time varies depending on the processing temperature, but
Usually, it is about θ minutes to IO hours.

In the present invention, it is preferable to have a hydrohalide salt of an organic base present during the above-mentioned contact treatment because the treatment time can be shortened. The organic base may be the same as that used in the production of the above-mentioned thiol carbonate, and the amount of the hydrohalic acid present is usually 0.7 to 2 times the mole of the thiol carbonate. In addition, when the reaction mixture is subsequently treated as it is, since the reaction mixture contains the hydrohalide salt of the organic base, there is no need to newly add it.

By the above-described treatment, the bis-byproduct contained in the thiol carbonate is converted into a thiol carbonate of pyrimidine thiol and aliphatic 7th alcohol. Since pyrimidinethiol is water-soluble, it can be easily removed by separating the aqueous phase after washing with water, and the target compound remains in a purified form in the organic solvent phase. Furthermore, the newly generated thiol carbonate has a different solubility and melting point from the target compound, the thiol carbonate of the general formula [...], so it is easily removed when the organic solvent phase is cooled and crystallized.

After the contact treatment, the mixture is usually washed with water of Q, co-/θ times the weight of the thiol carbonate about 7-/θ times, preferably at a low temperature of 23°C or less, and then crystallized according to a conventional method. Crystals of thiol carbonate of general formula [I[] are precipitated and then collected.

According to the present invention, bis-byproducts can be easily removed from the thiol carbonate obtained by the reaction, and as a result, thiol carbonate crystals of still higher purity can be recovered.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example/~3 It has a stirrer and a degree regulator. 2 into the reactor, tθr
99.91 (hecomoles) of t-phthylated col and 99.91 (hecomoles) of pyridine were charged, and while maintaining the temperature in the reaction system within the range of 30°C ± 3°C, t-dimethylpyrimidyl alcohol was added. Heptane solution A IIC containing all chloroformate, 20 U, &# (/, 0 mol)
? g was added dropwise over 3 hours with stirring, and the reaction was further carried out at the same temperature for 1 hour.

After the reaction is complete, add the alcohols shown in Table 1 to the reaction mixture. 7
1 was added thereto, and contact treatment was carried out under stirring at a temperature of 15°C for 1 hour.

After the contact treatment, water t and ooy were added to the mixture and the mixture was washed with water, separated into an organic phase and an aqueous phase, and the organic phase was further diluted with water booI.
It was washed three times in the same manner with I. Then, carbonate crystals were precipitated, which were then separated and dried under reduced pressure at room temperature.

For the crystals thus obtained, the yield and content of bis-form by-products relative to the raw material thiol chloroformate were evaluated, and the results shown in Table 1 were obtained.

Comparative Example/In the method of Example 1, 700 g of the crystals recovered in Table 1 Example q of Comparative Example 1 were added to Hebutanko S.
After dissolving in Og, 3! methanol at a temperature of r°C: 1
After the 0 treatment, 09 was added to the mixture and washed with water, the organic phase and the aqueous phase were separated, and the organic phase was washed 3 times in the same manner, and then The organic phase was cooled to Q'c and purified crystals were collected.

When the content of bis body by-products in the thus obtained crystals was measured, the results shown in Table 2 were obtained.

Table 2 Example S In the same reactor as in Example 1, P-methoxybenzyl alcohol l-41,j II (0.9 mol), pyridine g
11I# (/, O11 mol) and methylene chloride 3θo
't,A-dimethylpyrimidyl-cortiol chloroformate/12. ．． A dibutyl ether solution 6θop containing 311 (0.9 mol) was added dropwise over 3 hours with stirring, and the reaction was further carried out at the same temperature for 3 hours.

After the reaction is completed, methanol age is added to the reaction mixture,
Stirring treatment was performed at a temperature of 70° C. for 4 hours.

After the treatment, the mixture was washed with 5% saline 3θ7I, separated into an organic phase and an aqueous phase, and the organic phase was further mixed with citric acid j 1? Water, containing #? 6.7.71 7 times, Wednesday 3
Washed twice with 0711.

Then, the collected organic phase was transferred to A! under reduced pressure. By heat treatment at a temperature below r℃, light boiling components mainly composed of methylene chloride, yo
After distilling off the oy, the remaining organic phase was cooled to 0°C,
Crystals of P-methoxybenzyl-'I,A-dimethyl pyrimidyl-corchiol carbonate were precipitated, and then separated and dried under reduced pressure at room temperature.

Table 3 shows the results of measuring the yield and bis-byproduct content of the thus obtained crystals in the same manner as in Example.

Comparative example λ ( Table 3

Claims (1)

[Claims] (1) In the presence of an organic base, a thiol chloroformate of 2-mercaptopyrimidines represented by the following general formula (f) (wherein R1 and R2 represent a hydrogen atom or an alkyl group) has a substituent. is reacted with optional be/zyl alcohol or aliphatic secondary or tertiary alcohol to form the following general formula (wherein R1 and R2 have the same meanings as in the above general formula, and R8 represents a substituent). In the method for producing a thiol carbonate of 2-mercaptopyrimidines represented by (representing a be/zyl group or an alkyl group that may be present), the obtained thiol carbonate is contacted with an aliphatic primary alcohol. 11 merkabutopirimiji y characterized by
A method for producing thiol carbonates.