JPH0344074B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention utilizes N, which is known as a therapeutic agent for schizophrenia.
-Regarding a method for producing methylspiperone. N-methylspiperone [1-oxo-2-methyl-4-phenyl-8-[3-(4-fluorobenzoyl)propyl-2,4,8-triaza-spiro(4,5)decane] has the formula It is suggested as an oral or parenteral drug for the treatment of schizophrenia, along with spiperone, which lacks a methyl group at the 2-position. It has been suggested or described that this compound can be obtained by methylating spiperone with methyl halide. However, the details are unknown. Thus, US Pat. No. 3,155,669 discloses reacting an alkyl halide or a quaternary ammonium alkyl-aryl halide with a spiperone type compound in the presence of a strong base such as sodaamide to prepare the corresponding 2-alkyl derivative. There is. This method requires a long reaction time, as seen in the example of ethylating an 8-benzylspiperone compound with ethyl bromide. It is also described that alkylation with a quaternary alkyl-arylammonium salt requires a longer time. Moreover, according to additional experiments conducted by the present inventors, these methods require complicated means for separation and purification of the target product, and the yield thereof is extremely low. In recent years, in the field of nuclear medicine, the usefulness of spiperone and methylspiperone labeled with ¹¹ C or ¹⁸ F, etc., has begun to attract attention as a mapping agent for dopamine receptors. However, since ¹¹ C has a short half-life (20.3 minutes), it is desirable to develop a synthetic method that can selectively synthesize ¹¹ C-labeled methylspiperone in a short period of time. Thus, Wagner et al. said that they found a method for synthesizing N- ¹¹ C methylspiperone using ¹¹ C-labeled iodomethyl, completing the process from generation of ¹¹ CH ₃ to synthesis within 55 minutes, but the details are unclear and the purpose is unclear. It does not even include identification information for the object. (Science Vol. 221, September issue, No. 1264-1266
page). The present inventors have also discovered a method for synthesizing N-methylspiperone using methyl halide (including ¹¹ C labeling) rapidly and in high yield, and have arrived at the present invention. The present invention provides an improved method for producing N-methylspiperone by reacting an alkali metal salt of spiperone with methyl halide, characterized in that the reaction is carried out in an anhydrous hydrocarbon solvent in the presence of a phase transfer catalyst. provide a method. The alkali metal salt of spiperone used in the present invention can be prepared by adding alkali metal amide such as sodium amide, alkali metal hydride such as sodium hydride to spiperone in an inert solvent, for example, according to the method described in US Pat. No. 3,155,669. It is produced when a strong base is reacted with a strong base at room temperature or under heating.
The amount of strong base used at this time is preferably equivalent. The solvent used in the above reaction and the next methylation step is an aromatic or aliphatic hydrocarbon, and examples thereof include benzene, toluene, xylene, heptane, hexane, heptane, octane, and the like. The phase transfer catalyst used in the present invention is an organic compound that usually has a catalytic effect on the reaction between two liquid layers consisting of an organic layer and an aqueous layer, such as quaternary ammonium salt compounds, phosphonium salt compounds, and sulfonium salt compounds. These are onium salt compounds and crown ether type compounds such as. Nevertheless, even if the reaction between spiperone and methyl halide is carried out in an organic phase-aqueous phase system in the presence of a phase transfer catalyst, the desired N-methylspiperone is not produced. Examples of phase transfer catalysts used in the present invention include the following compounds, but the present invention is not limited to the use of these examples. Quaternary ammonium salts: (CH ₃ ) ₄ NBr Tetramethylammonium bromide (C ₃ H ₇ ) ₄ NBr Tetrapropylammonium bromide (C ₄ H ₉ ) ₄ NI Tetrabutylammonium iodide C ₆ H ₅ CH ₂ N (C ₂ H ₅ ) ₃ Br Benzyltriethylammonium bromide (C ₈ H ₁₇ ) ₃ NCH ₃ Cl Trioctylmethylammonium chloride (C ₄ H ₉ ) ₄ NHSO ₄ Tetrabutylammonium hydrogen sulfate quaternary phosphonium salt: (C ₆ H ₅ ) ₃ PCH ₃ Br Methyltriphenylphosphonium bromide (C ₄ H ₉ ) ₄ PBr Tetrabutylphosphonium bromide quaternary sulfonium salt: C ₆ H ₅ S (CH ₃ ) ₂ Cl Dimethylphenylsulfonium chloride crown ether type Compounds: Dicyclohexyl-18-crown-6 18-crown-6 Dibenzo-18-crown-8 In the methylation process, the alkali metal salt of spiperone can be used as it is in the form of a solution after the reaction to form it, but if the solvent is It is also possible to distill off the alkali metal salt, isolate the alkali metal salt as a powder, store it in a dry state, and provide the required amount to the reaction at the time of use. This specification describes a method using spiperone sodium salt powder. The solvent is preferably distilled off to dryness under reduced pressure in order to maintain the temperature at a low temperature, although it depends on the type of solvent. Sodium salts are commonly used as alkaline salts, but other salts can also be used. The amount of catalyst to be used is 1 to 100%, preferably 1 to 10%, based on spiperone, which is sufficient, but even if the amount exceeds this, the reaction will not be inhibited. The methyl halide used in the methylation step is typically iodomethyl, but methyl chloride or methyl bromide can also be used. The amount used is preferably from equivalent to 1.2 times equivalent to spiperone. The reaction is carried out in the solvents mentioned above, preferably in an anhydrous system. Even if water is present, the system must not form two layers with the solvent. This is contrary to the normal operation of phase transfer catalysts and is a noteworthy feature of the present invention. However, there is no need to particularly dehydrate the solvent, and commercially available solvents can be used as they are. The reaction temperature is 0~
A temperature of 120°C, preferably room temperature to 80°C, is used; lower temperatures outside this range will slow down the reaction rate, and higher temperatures will promote side reactions. In the present invention, under the above reaction conditions, 10
At least 40% of the used spiperone can be converted to its N-methyl form within a reaction time of minutes, and the target product can be quickly and easily recovered from the reaction mixture in purified form. Isolation and purification of N-methylspiperone can be carried out by commonly used methods. That is, by adding water after the reaction and removing water-soluble substances, unreacted spiperone and N-methylspiperone can be obtained from the organic layer, which can be subjected to silica gel column chromatography, high performance liquid chromatography, or preparative thin layer chromatography. Highly purified N-
Methylspiperone is obtained. Further, the direct reaction mixture can be easily isolated and purified using silica gel column chromatography, high performance liquid chromatography, or preparative thin layer chromatography. In particular, the latter method is an effective purification method when synthesizing from extremely small amounts of alkali metal salts.
It is a powerful means for the synthesis of ¹¹ C-N methylspiperone. The developing solution for column chromatography and thin layer chromatography is preferably acetonitrile/water (4/1) or acetonitrile/ethyl acetate/methanol (8/8/1). Thin layer chromatography can be advantageously used when the reactants are small. For high performance liquid chromatography, use 55% methanol as the developing solution for the ODS reverse phase column. The resulting methylspiperone has a melting point of 135-137℃
(When left in the air, it becomes carbonate with a melting point of 233-235
It is a white crystal that exhibits a temperature of ℃, and its infrared absorption spectrum is shown in Figure 1. Also, this one is ¹³ C−
The NMR (CDCl ₃ , 25MH ₂ ) spectrum shows a signal of N-CH ₃ that is not present in spiperone at δ=|27.5|, suggesting its structure. The N- ¹¹ CH ₃ substituted product of spiperone can also be produced in exactly the same manner, except that ¹¹ C-labeled methyl halide is used. ^11C -labeled methyl halide, _for example ^11CH3 , is produced by passing carbon through a cyclotron and reacting with ^11C and oxygen to produce ^11CO2 _.
This can be easily and quickly produced by reacting it with lithium ammonium hydride and hydrogen iodide, so it can be trapped in a solvent immediately after production, and then labeled methylspiperone can be quickly obtained by the method of the present invention. be able to. The automatic synthesis equipment for ¹¹ CH ₃ including the cyclotron is described in "Image Information (M) (from March 1981, p. 385) and Sumitomo Heavy Industries Technical Report (Vol. 30, No. 89, p. 76)". The N-alkylation reaction of amides using the phase transfer catalyst of the present invention can be used not only for the present compound but also for many useful compounds as ¹¹ C-N-methylation and N-methylation reactions, and can be performed in a short time. We believe that it will be possible to achieve the objective with high yield.Furthermore, the method of the present invention can be implemented even in hospitals equipped with small cyclotrons, and the present invention is useful not only in the medical world but also in the nuclear medicine society. We believe that the present invention greatly contributes to the development of the present invention.Next, embodiments of the present invention will be explained using examples and reference examples, but the present invention is not limited thereto.Example 1 General synthesis method: In a reaction flask Weigh out the sodium salt of spiperone (2 g) and tetra-n-butylammonium bromide (0.2 g), and add toluene (5 ml).
was added, injected with iodomethyl (0.86 g), and heated to 50°C.
Stirring was continued for 10 minutes while heating at . After the reaction, water (1 ml) was added to separate the organic layer and the aqueous layer, and the aqueous layer was further extracted twice with toluene (5 ml). The organic layers were collected and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography with solvent (acetonitrile/ethyl acetate/methanol).
1.76 g of N-methylspiperone crystals and 0.19 g of spiperone were obtained. The melting point of N-methylspiperone was |135-137|°C. Infrared absorption spectrum of N-methylspiperone (equipment used, Hitachi
295 type) is shown in Figure 1. Also | ¹³ C- | NMR spectrum (equipment used: JEOL Ltd. | JNM-FX100
|) is shown in Figure 4. In this spectrum, an N-CH ₃ signal not found in spiperone was shown at δ=|27.5|. For reference, high-performance liquid chromatography of the crude product (55% methanol, equipment used, Hitachi 635A)
Figure 2 shows the spectra of 635M type and 635M type. The elution times of spiperone, N-methylspirone, and toluene were 6.8 minutes, 7.9 minutes, and 29 minutes, respectively. Example 2 Micro-synthesis method: Weigh out the sodium salt of spiperone (5 mg) and tetra-n-butylammonium bromide (5 mg) into a 4 ml vial, add ¹¹ C-iodomethyl (0.8 ng,
After adding 50 mCi (equivalent to 50 mCi), the mixture was heated to 50°C and reacted for 5 minutes. Immediately after the reaction, the mixture was filtered through a membrane filter (0.22 μm), and the eluate was subjected to high performance liquid chromatography (55% methanol) to separate the N-methylspiperone portion. The separated liquid was concentrated under reduced pressure to obtain ¹¹ C-N-methylspiperone powder. The time required from the start of the reaction to isolation and collection is within 20 minutes. When the radioactivity of the container containing the ¹¹ C-N-methylspiperone powder was measured using a NaI-well counter, it was found to be 22.5 mCi (45 mCi due to half-life correction) at 20 minutes after the start of synthesis, and the yield was 90% ( vs. ¹¹ CH ₃
). FIG. 3 shows a spectrum obtained by a radioactivity detector (Canberra Model 802-3 and Canberra Series 30) during analytical fractionation using high-performance liquid chromatography. The spectrum shown is confirmed to be ¹¹ C-N-methylspiperone based on the elution time, and it also elutes earlier.
No impurities were generated, including the spectrum of ¹¹ CH ₃ , and the radiochemical purity of the filter eluate was
It was 100%. Example 3 Example 1 was repeated. However, as a catalyst, tetra-n-butylphosphonium bromide (1), tetra-n-butylammonium hydrogen sulfate (2), or 18-crown-6 (3) was used instead of tetra-n-butylammonium bromide. . That is, the sodium salt of spiperone (2 g) and the above catalyst (0.2 g) were weighed into a reaction flask, toluene (5 ml) was added, iodomethyl (0.86 g) was injected, and stirring was continued for 10 minutes while heating at 50°C. . After the reaction, water (1 ml) was added to separate the organic layer and the aqueous layer, and the aqueous layer was further extracted twice with toluene (5 ml). The organic layers were collected and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography eluting with solvent (acetonitrile/ethyl acetate/methanol) to give N-methylspiperone and spiperone with the following results.

Table Example 4 Example 1 was repeated. However, the reaction temperature is 50
20°C or 110°C was used instead of °C. That is, weighed the sodium salt of spiperone (2 g) and tetra-n-butylammonium bromide (0.2 g) into a reaction flask, added toluene (5 ml),
Inject iodomethyl (0.86g) and at the above temperature.
Stirring was continued for 10 minutes. After the reaction, add water (1 ml),
Separate the organic layer and aqueous layer, and add toluene (5 ml) to the aqueous layer.
Extracted twice. The organic layers were collected and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography eluting with solvent (acetonitrile/ethyl acetate/methanol) to give N-methylspiperone and spiperone with the following results.

[Table] Reference example 1 10 g (0.025 mol) of spiperone and 1 g (0.025 mol) of sodium hydride (purity 55%) were added to 20 ml of toluene and heated at 50°C in a moisture-proof atmosphere.
Spiperone Na salt was generated at ~55°C with stirring for 1 hour. The reaction solution was once depressurized and evaporated to dryness to obtain powder crystals. A portion of 2 g (0.005 mol) of this crystal was dissolved in 5 ml of toluene and 0.86 g (0.005 mol) of iodomethyl
was added and heated to 50-55°C for 180 minutes. After the reaction, water was added to stop the reaction, the organic layer was collected, the aqueous layer was extracted twice with 10 ml of toluene, and the organic layers were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (developing solution: acetonitrile/methanol =
4/1), and the resulting spiperone fraction and methylspiperone fraction were concentrated and crystals were collected. As a result, 1.1 g of spiperone and 0.1 g of methylspiperone were obtained. At the stage of crystal collection, the unreacted rate of spiperone was 55%, and the rate of methylspiperone production was 5.6%. Similarly, when the reaction was carried out for 10 minutes, the unreacted rate of spiperone was 71%, or methylspiperone was not produced and could not be recovered. Reference example 2 ¹¹ CH ₃ synthesized using a cyclotron
Add 1 ml of anhydrous toluene in which 0.8 ng (2 x 10 ^-12 mol) (50 mCi) was trapped to 5 mg (1.3 x 10 ^-5 mol) of sodium salt of spiperone (raw material crystals from Reference Example 1), and heat to 50 to 55°C. The mixture was heated and the methylation reaction was carried out for 10 minutes. Filter the reaction solution through a membrane filter (0.22μm)
The unreacted ¹¹ CH ₃ was removed by high performance liquid chromatography to remove undissolved substances, and the result was detected using a ^radio counter.
The yield of labeled methylspiperone is 1.2% and 2.8
% remained as a residue on the filter. High-performance liquid chromatography uses an ODS reverse phase column,
A 55% methanol solution was used as a developing solution. Reference Example 3 This reference example shows that the phase transfer catalyst used in the present invention does not function in a solvent-water two-layer system. 2 g (0.005 mol) of spiperone in 5 ml of toluene,
2.5ml of 0.2N sodium hydroxide aqueous solution, Tetra-n
- Add 0.2 g of butylammonium bromide and 0.86 g (0.005 mol) of iodomethyl, and add 50 to 55°C.
and reacted for 10 minutes and 60 minutes, respectively. The recovery step after the reaction was performed in the same manner as in Reference Example 1,
I got the following results.

[Table] It was assumed that most of the spiperone was converted into quaternary chloride due to side reactions.

[Brief explanation of drawings]

Figure 1 shows the infrared absorption spectrum of methylspiperone obtained by the method of the present invention (KBr tablet forming method).
shows. FIG. 2 shows high performance liquid chromatography spectra of N-methylspiperone and spiperone. Figure 3 shows N- ¹¹ C using the radioactive element ¹¹ C.
The high performance liquid chromatography spectrum of methylspiperone is shown. Figure 4 shows the ^13C -NMR spectrum of N-methylspiperone (CDCl ₃ , 25MH ₂ ).
shows.

Claims (1)

[Claims] 1. A method for producing N-methylspiperone, which comprises reacting an alkali metal salt of spiperone with methyl halide in a hydrocarbon solvent in an anhydrous system in the presence of a phase transfer catalyst. 2 Claim 1 in which the catalyst is a quaternary ammonium salt compound, a phosphonium salt compound, a sulfonium salt compound, or a crown ether type compound
The method described in section. 3. The method according to claim 2, wherein the quaternary ammonium salt compound is tetra-n-butylammonium bromide or tetra-n-butylammonium hydrogen sulfide. 4 Claim 2, wherein the phosphonium salt compound is tetra-n-butylphosphonium bromide
The method described in section. 5 Crown ether type compound is 18-crown-
6. The method according to claim 2, wherein the method is: 6. The method according to claim 1, wherein the methyl halide is iodomethyl. 7. The method according to claim 6, wherein the mode methyl is ¹¹ C-labeled iodomethyl.