JPS60188384A - Production of n-methylspiperone - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a remedy for schizophrenia, in a short time in high yield, by reacting an alkali metal salt of spiperone with a methyl halide in a hydrocarbon solvent in the presence of a phase-transfer catalyst. CONSTITUTION:An alkali metal salt of spiperone is made to react with a methyl halide (e.g. methyl iodide, methyl chloride, etc.) in the presence of a phase- transfer catalyst selected from a quaternary ammonium salt compound such as tetra-n-butyl ammonium bromide, a quaternary phosphonium salt compound such as tetra-n-butyl phosphonium bromide, and a crown ether compound such as 18- crown-6. The reaction is carried out in a hydrocarbon solvent under anhydrous condition at 0-120 deg.C, preferably at room temperature - 80 deg.C. The amount of the catalyst is 1-100%, preferably 1-10% based on the spiperone.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N-methylsubiperone, which is known as a therapeutic agent for schizophrenia.

N-methylspiperone [1-oxo-2-methyl-4-
Phenyl-8-(3-(4-fluorobenzoyl)propyl-2,4,8-triaza-spiro(4,5)decane) has the formula and can be used orally or with spiperone lacking a methyl group in the 2-position. It is suggested as a parenteral drug for the treatment of schizophrenia. It has been suggested or described that this drug can be obtained by methylating spiperone with methyl halide. However, the details are unknown. Namely, U.S. Patent No. 3
, 155,669 discloses the reaction of alkyl halides or quaternary ammonium alkyl-aryl halides with spiveronic compounds in the presence of a strong base such as sodaamide to produce the corresponding 2-alkyl derivatives. There is. This method requires a long reaction time, as seen in the example of ethylating an 8-pendylsubiperone 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 use of spiperone and methylspive[1] labeled with C or 18F has begun to attract attention as mapping agents for dopamine receptor 1. However, 11C has a short ``1'' life (20,
(3 minutes), it is therefore desirable to develop a synthetic method that can selectively synthesize 110-labeled methylspiperone in a short period of time. (Wagner et al. use 11C-labeled iodomethyl
-, 11c methylspiperone 1 was synthesized. From generation to synthesis of Cl-131, 55
It is said that they have found a method that can complete the process within minutes, but the details are unclear [they do not even include identification data for the object. (
Science Vol. 221, September issue, No. 1264-1266
page).

The present inventors also discovered a method for rapidly synthesizing N-methylspiperone using methyl hegenide (including 11Ca7!), and arrived at the present invention.

The present invention is a method for producing N-methylspipe[1] by reacting an alkali metal salt of subiperone with methyl halide, which is characterized in that the reaction is carried out in an anhydrous hydrocarbon solvent in the presence of a phase transfer catalyst. Provide an improved method.

The alkali metal salt of subiperone used in the present invention can be prepared by adding spiperone to an alkali metal amide such as sodium amide, an alkali metal amide such as sodium hydride, etc. in an inert solvent, for example, according to the method described in U.S. Pat. It is produced when reacting with a strong base such as a metal hydride in a groove or on heating. The amount of strong base used at this time is preferably equivalent.

The solvent used in the above reaction and the following methylation is as follows:
Aromatic or aliphatic hydrocarbons, examples of which include benzene, toluene, xylene, heptane, hexadi, 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 5- is carried out in an organic phase-aqueous phase system in the presence of a phase transfer catalyst, the desired N-methylsubiperone 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 salt: (CH3)4NBr Tetramethylammonium bromide (C31-17)4NBr Tetrapropylammonium bromide (C4-19
) 4 N I Tetrabutylammonium iodide CHCHN (C
2H5) 3Br 5 2 benzyltriethylammonium bromide (CH)
NGH3C,e 113 trioctylmethylammonium chloride (CH) N
+SO4 94 Tetrabutylammonium hydrogen sulfate quaternary phosphonium salt: 6- Quaternary sulfonium salt: C6H55(C1]3)2C,Il Dimethylphenylsulfonium chloride crown ether type compound dicyclohexyl-18-crown- 618-crown-6 dibenzo 18-crown-8 In the methylation step, the alkali metal salt of spiberone can be used as it is in the form of a solution after the reaction to form it, but it is also possible to distill off the solvent and turn the alkali metal salt into a powder. It can also be isolated and stored in a dry state, and the required amount can be added to the reaction at the time of use. This specification describes a method using the sodium salt powder of Subiperone. Although the solvent may be distilled off to dryness depending on the type of solvent, it is preferable to remove the solvent under reduced pressure in order to maintain the temperature at a low temperature. Sodium salts are commonly used as alkaline salts, but other salts can also be used. It is sufficient that the catalyst used is 1 to 100%, preferably 1 to 10%, based on spiperone.
Exceeding this will not harm the reaction.

A typical example of methyl hegenide used in the methylation step is iodomethyl, but methyl chloride or methyl bromide can also be used. The amount of suspension used is preferably 1.2 times the equivalent of 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 a two-layer with the solvent. This is contrary to the normal operation of phase transfer catalysts and is a noteworthy feature of the present invention. However, it is not necessary to specifically dehydrate the solvent, and commercially available solvents can be used as they are. The reaction temperature i is 0 to 120°C, preferably room temperature to 80°C; low temperatures outside this range slow down the reaction rate, and high temperatures promote side reactions.

In the present invention, at least 40% of the used subiperone can be converted to its N-methyl form in the reaction time of less than 10 minutes under the above-mentioned reaction bed A'], and the target product can be quickly and easily extracted from the reaction mixture. It can be easily recovered in purified form.

Isolation and purification of N-methylspiperone can be carried out by commonly used methods. That is, after the reaction, water is added,
By removing water-soluble substances, unreacted spiperone and N-methylspiperone are obtained from the organic layer, and highly purified N- Methylspiperone is obtained. Further, the direct reaction mixture can be easily isolated and purified by using silica gel column chromatography, high performance liquid chromatography, and preparative thin layer O-mathography. In particular, the latter method is an effective purification method in the case of synthesis from a very small amount of alkali metal salt, and is an effective means for the synthesis of 11C-N methylsubiperone. The developing solution for column chromatography and thin layer chromatography is preferably acetonitrile/water (4/1) or acetonitrile/9-tyl acetate/methanol (8/8/1) system. Thin layer chromatography can be used to advantage when the reactant is raw rock. In the case of high-performance liquid lithography [171-graphy], use 55% methanol as a developing solution for an ODS reverse phase column.

The obtained methylspiperone is a white crystal with a melt temperature of 233 to 235°C (reference: subiperone 20/1°C), and its infrared absorption spectrum is shown in FIG. Also this one is NM
The R (CDC, i!3') spectrum shows a signal of N-CI-13, which is not found in subiveron, at δ-2,95, suggesting its structure.

111 An N-CH3 substituted product of spiberone can also be produced in exactly the same manner except that C-labeled methyl halide is used. 11C-labeled methyl halide 1 For example, CI-(31 can be easily produced by passing carbon through a cyclotron, reacting 11C produced with oxygen to form 11CO, and reacting this with lithium aluminum hydride and hydrogen iodide. Since it can be produced rapidly, it can be trapped in a solvent immediately after production, and then labeled methyl 10-spiperone can be obtained quickly by the method of the present invention. [Described in Video Information (M) (from 3/198L, page 385) and Sumitomo Heavy Industries Technical Report (Vol. 30, No. 89, page 76).

The N-alkylation reaction of amides using the phase transfer catalyst of the present invention not only produces the present compound but also one of many useful compounds.
10] We believe that it can be used for N-methylation and N-methylation reactions, and that it will be possible to achieve the purpose in a short time and with high yield. Furthermore, the method of the present invention can be implemented even in hospitals equipped with small cyclotrons.
We believe that the present invention will greatly contribute not only to the medical community but also to academic medical societies.

Next, the present invention will be explained in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 General synthesis method: In a reaction flask, add spiperone sodium salt (2 g), tetra-n-butylammonium 11-um bromide (0.2 g), toluene (5-)
and 411 g of iodomethyl (0.86 rl) were added, followed by stirring for 10 minutes while heating at 50°C.

Reaction water (1d) was added to separate the organic and aqueous layers (', l), and the aqueous layer was further extracted twice with toluene (5 mQ). The organic layers were collected and concentrated under reduced pressure to obtain a crude product. The crude product was applied to a silica gel column chroma 1 hegelafie and dissolved vA (
Elute with acetonitrile/ethyl acetate/methanol).
1.76g of N-methyl subiperone crystals and 0 subperone
．． 19g was obtained. The melting point of N~methylspiverone is 233
The temperature was ~235°C. The infrared absorption spectrum of N-methylspiperone (equipment used: Hitachi model 295) is shown in FIG.

In addition, the proton NMR spectrum (equipment used, JEOL, PMX-60) showed an N-CH3 signal at δ-2,95, which is not present in subiperone. For reference, the spectrum of the crude product obtained by high performance liquid chromatography (55% methanol, equipment used, Hitachi 635A and 635M) is shown in Figure 2.
Shown below. The elution times of subiperone, N-methylspirone, and toluene were 6.8 minutes, 7.9 minutes, and 29 minutes, respectively.

Example 2 Micro-open synthesis method = Weigh out sodium salt of spiperone (5 mg) and Teller n-butylammonium bromide (5 my) into a 4-size vial, and add 11 Idl of toluene.
11C-iotomedel (0,8no, 50
(corresponding to mC1) was added thereto, and then heated to 50°C and reacted for 5 minutes. Immediately after the reaction, filter membrane filter (0,22
The eluate was subjected to high performance liquid chromatography (5 μm) and the eluate was subjected to high performance liquid chromatography (5 μm).
5% methanol) to separate the N-methylspiperone portion. The separated liquid was concentrated under reduced pressure to obtain 11c x-methylsubiperone powder. The time required for isolation and collection from the start of the reaction is within 20 minutes. When the radioactivity of a container containing 11C-N-methylsubiperone powder was measured using a Nal-well counter, it was found that 22.5 m was detected 20 minutes after the start of synthesis.
C1 (451 mci with half-life correction) and the yield was 90% (vs. CH3I).

13- Figure 3 shows the spectrum detected by the radioactivity detector (Canberra Model 802-3 and Canberra Series 30) during analytical fractionation using high-performance liquid chromatography. The spectrum shown is 11 c from the elution time.
It was confirmed that it was x-methylsubiperone, and no impurities were generated, including the spectrum of C1-131, which elutes earlier, and the radiochemical purity of the filter eluate was 100%.
%Met.

Example 3 Example 1 was repeated. However, as a catalyst, tetralar〇-
Butylammonium hydrogen sulfate (2)
Or 18-crown-6 (3) was used.

That is, the reaction flask was filled with 1 to 2 salts of Subiperone.
g), weigh out the above catalyst (0.2g) and add toluene (5ml
and inject iodomethyl (0,869).
Stirring was continued for 10 minutes while warming at °C. Reaction water contact (1
-) was added to separate the organic layer and the aqueous layer, and the aqueous layer was further extracted twice with toluene (5d). 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 using solvent (
Elute with acetonitrile/ethyl acetate/methanol).
N-methylspiperone and spiverone were obtained with the following results.

Catalyst N-Methylsubi Spiperone Perone Yield Recovery Amount (111.20g 0.70q (60%) (35%) +21 0.84g 0.88g (42%) (44%) +31 1.64!7 0.289 ( (82%) (14%) Example 4 Example 1 was repeated, except that instead of 50°C, 20°C or 110°C was used as the reaction temperature.

Namely, the sodium salt of spiverone (2 g) was added to the reaction flask.
, tetra-n-butylammonium bromide (0.2g
), toluene (5-) was added thereto, iodomethyl (0.86 g) was injected, and stirring was continued at the above temperature for 10 minutes. After the reaction, water (1d) was added, and the organic layer and aqueous layer were diluted with 1 heluene (51d) for 2 minutes.
Extracted twice. The organic layer was collected and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chroma 1-graphie and eluted with a solvent (acetonitrile/ethyl acetate/methanol) to obtain N-methylspiperone and spiperone with the following results.

21nlff N-Methylspi Spiberone Yield Recovery amount 20°C 1.22g 0.6g (61%) (30%) 110°C 1.42g 0.46g (71%) (23%) Reference Example 1 Spiberone 10g (0,025 mol) and sodium hydride (55% pure melon) 1 g (0,025 mol) were added to 20 d of toluene, and the mixture was heated at 50°C in a moisture-proof atmosphere.
The Na salt of spiperone was formed at 55° C. with stirring for 1 hour. The reaction solution -
D The mixture was evaporated to dryness under reduced pressure to obtain powder crystals.

A portion of 2 g (0,005 mol) of this crystal was added to 51 mol of toluene.
1+1! 0.86 g (0,005 g) of iodomethyl dissolved in
mol) was added and heated to 50 to 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 d of toluene, and the organic layers were combined and concentrated under reduced pressure.

The crude product was separated using silica gel column chroma 1 to (developing solution: acetonitrile/methanol-4/1), and the resulting spiberone fraction and methylsubiperone fraction were concentrated to collect crystals. As a result of step (a), 1.1 g of spiperone and 0.1 g of methylspiperone were obtained. At the stage of crystal collection, the rate of unreacted 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%, and methylsubiperone was not produced and could not be recovered.

17- Reference Example 2 1me of anhydrous toluene in which 0.8no (2X10-12 mol) (50mCi) was trapped was mixed with 5nog (1,3x1
0'mol) and heated to 50 to 55°C to carry out a methylation reaction for 10 minutes. Pass the reaction solution through a membrane filter (0
, 22!1m> to remove undissolved substances, and separated by high-speed liquid chromatography [71-graph]. When detected with a radio counter, unreacted 110H3■ accounted for 96%, and the produced 1
The yield of 1G-labeled M. gills viperon was 1.2%, and 2
．． 8% remained as a residue on the filter. High-performance liquid chromatography was performed using an ODS reverse phase column and a 55% methanol solution 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.

g) Li En5 #11! k-spiverone 2g (0
,005-El), 2.5 d of 0.2N aqueous sodium to lithium hydroxide solution, 0.2 q1 of 18-tetra-n-butylammonium bromide and 0.86 g (0,005 mol) of iodomethyl were added,
The mixture was heated to 50-55°C and allowed to react for 10 minutes and 60 minutes, respectively.

The recovery step after the reaction was performed in the same manner as in Reference Example 1, and the following results were obtained.

Reaction time Methylspiperonperone Yield Recovery (rate) 10 minutes No formation observed 0.4g (20%) 60 minutes Same as above 0. 26 g (13%) It was estimated that most of Subiperone was converted into quaternary chloride due to side reactions.

[Brief explanation of the drawing]

FIG. 1 shows an infrared absorption spectrum of methylspiperone obtained by the method of the present invention (KBr tablet forming method). FIG. 2 shows high performance liquid chromatography spectra of N-methylsubiperone and subiperone. 19- Figure 3 shows the high performance liquid chromatography spectrum of x 11 c methylsubiperone using the radioactive element 11C. Agent Hiroshi Asari 20-

Claims (7)

[Claims] (1) A method for producing N-methyl subiperone, which comprises reacting an alkali metal salt of subiperone and methyl halide in a hydrocarbon solvent in an anhydrous system in the presence of a phase transfer catalyst. (2) The method according to claim (1), wherein the catalyst is a quaternary ammonium salt compound, a phosphonium salt compound, a sulfonium salt compound, or a crown ether type compound. (3) The method according to claim (2), wherein the quaternary ammonium salt compound is tetra-n-butylammonium bromide or tetra-n-butylammonium hydrogen sulfate. (4) The method according to claim (2), wherein the phosphonium salt compound is tetra-n-butylphosphonium bromide. (5) The crown ether type compound is 18-crown-
The method according to claim (2), which is 〇. (6) The method according to claim (1), wherein the methyl halide is iothmedel. (7) The method according to claim (6), wherein the iodomethyl is 11G-labeled iodomethyl.