KR101269588B1 - Azetidinium salt as fp-cit precursor, selective preparation method thereof, and synthesis of fp-cit - Google Patents
Azetidinium salt as fp-cit precursor, selective preparation method thereof, and synthesis of fp-cit Download PDFInfo
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- 0 COC([C@](C(CC1)N(CCCOS(*)(=O)=O)C1C1)C1c(cc1)ccc1I)=O Chemical compound COC([C@](C(CC1)N(CCCOS(*)(=O)=O)C1C1)C1c(cc1)ccc1I)=O 0.000 description 1
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
Abstract
FIELD OF THE INVENTION The present invention relates to azetidinium salts of N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane compounds, methods for their preparation and applications In more detail, N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane compound is dissolved in a polar solvent and heated to N- (3 Provided is a method for selectively preparing an azetidinium salt of a -sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane compound. It can be applied as an effective precursor for the production of diagnostic [ 18 F] FP-CIT for positron emission tomography.
Description
FIELD OF THE INVENTION The present invention relates to azetidinium salts as FP-CIT precursors, selective preparation thereof and the synthesis of FP-CIT.
Dopamine is a catecholamine that acts as a neurotransmitter in the brains of various animals, including humans, and is known to be involved in various mental disorders. In patients with schizophrenia, dopamine-induced neurotransmission is increased, while dopamine-induced neurotransmission decreases Parkinson's disease, which is accompanied by dyskinesia.
Dopamine secreted at the end of presynaptic cells passes through a synapse and binds to a dopamine receptor located at the end of the nerve cell to transmit a signal, followed by dissociation from the receptor and located at the end of the systemic cell It is reabsorbed through the transporter. Dopamine receptors and transporters are widely distributed in the striatum located in the midbrain, and in patients with Parkinson's disease, the concentrations of transporters are significantly reduced compared to normal people. Therefore, researches on Parkinson's disease diagnostic drugs using compounds that bind strongly to the dopamine transporter have been continuously conducted. Positron emission tomography, a diagnostic imaging technique in the field of nuclear medicine using radioisotopes, is a very useful molecular imaging technique that can detect biochemical changes and diagnose diseases early. Among the various radioisotopes emitting positrons, fluorine-18 is the most studied because of its ease of mass production, low positron energy, high specific activity and moderate half-life of 110 minutes.
Fluorine-18 labeling compounds developed specifically for the diagnosis of Parkinson's disease by specifically binding to the striatum include [ 18 F] fallypride and [ 18 F] FESP, which bind to dopamine receptors. tropane derivatives have been reported with [ 18 F] FECNT, [ 18 F] FP-CIT, [ 18 F] LBT999 and the like.
Among these, [ 18 F] FP-CIT is known to be easy to synthesize, chemically stable, and give good human images. Therefore, many synthetic and clinical studies have been conducted, and it has been approved by the Korea Food and Drug Administration in Korea. It is used.
In the case of the tertiary amine substituted with a propyl having a leaving group X at the terminal, it has been reported that an azetidinium salt having a tetracycle is formed through an intramolecular cyclization reaction as shown in the above figure. Nucleophilic substitution reactions have been reported (VR Gaertner, J. Org. Chem ., 33 (2), 523-530, 1968; HM Zacharis, J. Am. Chem. Soc ., 93 (12), 1935 -1938, 1971; A. Bakalarz, Tetrahedron , 55, 12211-12226, 1999; DO Kiesewetter , J. Labelled Compd . Radiopham ., 47, 953-969, 2004; WO 90/08131; F. Couty, O. David, F. Durrat, G. Evano, S. Lakhdar, J. Marrot, M. Vargas-Sanchez, Eur . J. Org . Chem . , 3479-3490, 2006.).
The present inventors observed that an additional polar compound is produced in the process of synthesizing and storing the FP-CIT precursor, and the separation / analysis confirmed that the compound is an azetidinium salt compound, and this is for preparing [ 18 F] FP-CIT. The present invention was completed by confirming that it could be a better precursor.
An object of the present invention is a precursor for the synthesis of N- (3-fluoropropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (hereinafter referred to as FP-CIT). It is to provide a novel azetidinium salt.
Another object of the present invention is to provide a novel formula 1 ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl) -2'-(methoxycarbonyl) spiro [azetidine-1, A method for preparing azetidinium salt represented by 8'-bicyclo [3.2.1] octane] -1- 옥 R-substituted sulfonate} with high purity.
Another object of the present invention is the nucleophilic fluorination reaction compared to the conventional precursor N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane It is shown to be a better compound.
In order to achieve the above object, the present invention provides an azetidinium salt represented by the following formula ( 1 ).
(In
* Compound name: ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl) -2'-(methoxycarbonyl) spiro [azetidine-1,8'-bicyclo [ 3.2.1] octane] -1- 윰 R-substituted sulfonate {( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl) -2'-(methoxycarbonyl) spiro [azetidine-1, 8'-bicyclo [3.2.1] octan] -1-ium R-substituted sulfonate}
In addition, the present invention provides a FP-CIT precursor represented by the following formula ( 1 ).
[Formula 1]
(In
In addition, the present invention provides a method for selectively preparing a compound represented by Chemical Formula 1 or Chemical Formula 2 using the polarity of the solvent, as shown in
[Reaction Scheme 1]
(In the
In addition, the present invention provides a method for preparing FP-CIT represented by the formula ( 3) through a nucleophilic fluorination reaction using the azetidinium salt represented by the formula ( 1) , as shown in
[Reaction Scheme 2]
(In
N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane, a precursor of [ 18 F] FP-CIT, has been used for chemical stability. This low, there was a disadvantage in that it is decomposed into various compounds during storage, the azetidinium salt according to the present invention can be prepared not only with high purity, but also has a high chemical stability characteristics that can be stored for a long time. In addition, FP-CIT can be synthesized at a much faster and higher yield in nucleophilic fluorination reaction, and thus can be useful for preparing [ 18 F] FP-CIT.
1 is a view showing a method for synthesizing a compound represented by Formula 1 and a reversible reaction with a compound represented by
2 is a view showing the ratio of the compound of
3 is a diagram showing the ratio of the compound of Formula 1b and the compound represented by Formula 2b according to the present invention in various solvents.
4 is a graph in which the compound of Formula 1 according to the present invention is distributed according to the polarity of the solvent.
5 is a graph showing a nucleophilic fluorination reaction using the compound represented by the formula ( 2b ).
6 is a graph showing a nucleophilic fluorination reaction using a compound represented by Chemical Formula 1b according to the present invention.
Hereinafter, the present invention will be described in detail.
The present invention is formula 1 {( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl) -2'-(methoxycarbonyl) spiro [azetidine-1,8'- An azetidinium salt represented by bicyclo [3.2.1] octane] -1- 윰 R-substituted sulfonate}.
[Formula 1]
In
In addition, the present invention provides a method for the selective preparation of a compound represented by Formula 1 or Formula 2 , as shown in
[Reaction Scheme 1]
In
According to the present invention, the azetidinium salt represented by the formula ( 1) is a compound represented by the formula (2) as in
In the method for preparing an azetidinium salt of the present invention, the
In addition, according to the present invention, the compound represented by Chemical Formula 2 may also be selectively prepared from an azetidinium salt represented by Chemical Formula 1 . In this case, a non-polar solvent having an E T N value of 0.20 or less may be used, and preferably benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, t -butyl methyl ether, dimethoxymethane , Diethoxymethane, carbon tetrachloride (CCl 4 ), and the like can be used.
Furthermore, the present invention provides a method for preparing FP-CIT through a nucleophilic fluorination reaction from the azetidinium salt represented by Chemical Formula 1 .
[Reaction Scheme 2]
In
The azetidinium salt represented by
Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are only for the purpose of illustrating the present invention, and the content of the present invention is not limited by the following examples and experimental examples.
Preparation Example 1 Preparation of N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (compound of Formula 2)
Step 1: Preparation of N- (3-hydroxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (5a)
nor-β-CIT ( 4 , 965 mg, 2.6 mmol) was dissolved in anhydrous toluene (60 mL) under argon gas, then 3-bromo-1-propanol (1.15 g, 8.3 mmol) and triethylamine (1.8 mL) ). The reaction mixture was heated to reflux for 4 hours, cooled to room temperature, the resulting solid was filtered off, and then toluene was removed under reduced pressure. Column chromatography with methanol / dichloromethane (8/92) gave the target compound N- (3-hydroxypropyl) -2-β-carbomethoxy-3-β- (4-iodo, a colorless liquid. Phenyl) tropane ( 5a , 1 g, 90%) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.50-1.82 (m, 5H), 2.00-2.20 (m, 2H), 2.40-2.48 (m, 1H), 2.53 (td, 1H, J = 12.8, 2.9 Hz ), 2.54-2.64 (m, 1H), 2.87-2.92 (m, 1H), 2.94-3.03 (m, 1H), 3.50 (s, 3H), 3.59-3.67 (m, 2H), 3.75-3,80 (m, 2H), 6.97 (d, 2H, J = 8.2 Hz), 7.57 (d, 2H, J = 8.6 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 24.8, 26.3, 29.0, 33.6, 33.8, 51.4, 53.0, 54.6, 59.2, 64.5, 64.8, 91.3, 129.4, 136.4, 142.2, 172.1
Step 2-1: Preparation of N- (3-methanesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (2a)
N- (3-hydroxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 5a , 102 mg, 0.24 mmol) obtained in
1 H NMR (400 MHz, CDCl 3 ) δ 1.60-1.88 (m, 5H), 1.94-2.15 (m, 2H), 2.30-2.42 (m, 2H), 2.50 (td, 1H, J = 12.4, 2.8 Hz ), 2.87-2.92 (m, 1H), 2.94-2.99 (m, 1H), 2.98 (s, 3H), 3.34-3.40 (m, 1H), 3.49 (s, 3H), 3.62-3.66 (m, 1H ), 4.24-4.38 (m, 2H), 6.99 (d, 2H, J = 8.4 Hz), 7.58 (d, 2H, J = 8.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 25.9, 26.0, 28.5, 33.8, 33.9, 37.0, 49.0, 51.1, 52.6, 61.5, 61.8, 62.8, 68.4, 91.1, 129.4, 136.9, 142.8, 171.9
Step 2-2: Preparation of N- (3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (2b)
N- (3-hydroxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 5a , 102 mg, 0.24 mmol) obtained in
1 H NMR (400 MHz, CDCl 3 ) δ 1.50-1.80 (m, 5H), 1.88-2.10 (m, 2H), 2.26 (t, 2H, J = 6.0 Hz), 2.30-2.40 (m, 1H), 2.45 (s, 3H), 2.80-2.94 (m, 2H), 3.18-3.25 (m, 1H), 3.41 (s, 3H), 3.54-3.60 (m, 1H), 4.05-4.20 (m, 2H), 6.96 (d, 2H, J = 8.0 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.57 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 21.8, 26.0, 26.1, 28.7, 33.9, 33.9, 49.4, 51.1, 52.7, 61.6, 63.1, 91.2, 126.1, 128.1, 128.7, 129.1, 129.6, 130.0, 133.3, 137.0 , 137.7, 143.1, 144.7, 171.8
Experimental Example 1 According to the solvent of N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane according to the solvent Generation of azetidinium salts
The present inventors N- (3- sulfonyloxy propyl) -2-methoxy-β- carbonyl -3-β- (4- iodo-phenyl) tropane compound of
Azeti, a polar compound produced from N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl)
As shown in Table 1, N- (3-sulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane compound represented by
In addition, the results of the distribution of the compound according to the solvent showed that the distribution ratio of the compound after the experiment was determined according to the polarity of the solvent used regardless of the distribution ratio of the compound before the experiment.
In the results of Table 1, in the case of toluene, benzene, and tetrahydrofuran, which are nonpolar solvents, a relatively nonpolar compound of
The results of Table 1 are listed according to E T N (the water is defined as 1.00, the tetramethylsilane is defined as 0.00 and the solvent is measured), which is a standard value representing the polarity of the solvent. Figure 4 is a graph showing the production rate of the azetidinium salt compound according to the polarity value of the solvent.
In addition, as shown in
< Example 1> Azetidinium Preparation of Salt (1a)
N- (3-methanesulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 2a ) obtained in step 2-1 of Preparation Example 1 was acetonite. After dissolving in a reel, the mixture was heated at 70 DEG C for 30 minutes and then the solvent was removed under reduced pressure. Again, it was dissolved in a small amount of dichloromethane, and then added with an excess of diethyl ether and centrifuged to give the white solid target compound azetidinium salt ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-IO Dophenyl) -2 '-(methoxycarbonyl) spiro [azetidine-1,8'-bicyclo [3.2.1] octane] -1-' methanesulfonate ( 1a ) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.93-2.18 (m, 3H), 2.35-2.58 (m, 3H), 2.74 (s, 3H), 2.75-2.90 (m, 2H), 3.14-3.22 (m , 1H), 3.23-3.30 (m, 1H), 3.57 (s, 3H), 4.16-4.25 (m, 1H), 4.25-4.33 (m, 1H), 4.55-4.67 (m, 2H), 4.78-4.90 (m, 2H), 6.98 (d, 2H, J = 8.4 Hz), 7.60 (d, 2H, J = 8.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 14.9, 23.0, 24.7, 27.1, 31.3, 39.6, 48.8, 52.6, 56.3, 64.3, 65.4, 68.1, 92.5, 129.0, 137.5, 138.6, 170.3
< Example 2> Azetidinium Preparation of Salt (1b)
N- (3-toluenesulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 2a ) obtained in step 2-2 of Preparation Example 1 was obtained by acetonite. After dissolving in a reel, the mixture was heated at 70 DEG C for 30 minutes and then the solvent was removed under reduced pressure. After dissolving again in a small amount of dichloromethane, excess diethyl ether was added and centrifuged to give a white solid target compound azetidinium salt ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodo Phenyl) -2 '-(methoxycarbonyl) spiro [azetidine-1,8'-bicyclo [3.2.1] octane] -1-' toluenesulfonate ( 1b ) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.84-2.14 (m, 3H), 2.33 (s, 3H), 2.36-2.50 (m, 3H), 2.70-2.82 (m, 2H), 3.12-3.26 (m , 2H), 3.48 (s, 3H), 4.13-4.28 (m, 2H), 4.50-4.62 (m, 2H), 4.74-4.84 (m, 2H), 6.93 (d, 2H, J = 8.4 Hz), 7.13 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.76 (d, 2H, J = 8.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 14.9, 21.3, 23.0, 24.6, 27.0, 31.3, 48.8, 52.4, 56.2, 64.3, 65.4, 68.2, 92.3, 125.9, 128.6, 129.0, 137.4, 138.7, 139.2, 144.1 , 170.3
In addition, the present invention carried out an experiment to confirm that the compounds represented by the
< Manufacturing example 2> 1,1- Die deuterium -3- ( Tetrahydropyranyloxy )profile Methanesulphone Preparation of Yite (9)
Step 1: t -Butyl 3- ( Tetrahydropyranyloxy ) Propionate (7)
t -butyl 3-hydroxypropionate ( 6 , 206 mg, 1.41 mmol) was dissolved in dichloromethane (9 mL) and then 3,4-dihydro-2 H -pyran (DHP, 142 mg, 1.69 mmol) ) And p -toluenesulfonic acid (14 mg, 0.07 mmol) were added and stirred at room temperature for 10 minutes. Saturated aqueous sodium hydrogen carbonate solution was added and the organic compound produced with dichloromethane was extracted. Then, column chromatography was carried out with ethyl acetate / n -hexane (1/9) to give the title compound t -butyl 3- (tetrahydro) as a colorless liquid. Pyranyloxy) propionate ( 7 , 324 mg, 99%) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 1.48-1.62 (m, 4H), 1.65-1.73 (m, 1H), 1.76-1.86 (m, 1H), 2.51 (t, 2H , J = 6.4 Hz), 3.48-3.55 (m, 1H), 3.65 (dt, 1H, J = 6.4, 10.0 Hz), 3.84-3.91 (m, 1H), 3.96 (dt, 1H, J = 6.4, 10.0 Hz), 4.63 (t, 1 H, J = 3.6 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 19.3, 25.4, 28.1, 30.5, 36.4, 62.0, 63.3, 80.4, 98.7, 171.0
Step 2: 1,1- Die deuterium -3- ( Tetrahydropyranyloxy ) Propanol (8)
The t -butyl 3- (tetrahydropyranyloxy) propionate ( 7 , 324 mg, 1.41 mmol) obtained in
1 H NMR (400 MHz, CDCl 3 ) δ 1.50-1.62 (m, 4H), 1.69-1.90 (m, 4H), 2.34 (brs, 1H), 3.50-3.56 (m, 1H), 3.58-3.64 (m , 1H), 3.84-3.91 (m, 1H), 3.91-3.98 (m, 1H), 4.58-4.62 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 19.6, 25.3, 30.6, 31.8, 62.5, 66.4, 99.1.
Step 3: 1,1- Die deuterium -3- ( Tetrahydropyranyloxy )profile Methanesulfonei Manufacture of meth 9
1,1-dihydrogen-3- (tetrahydropyranyloxy) propanol ( 8 , 216 mg, 1.33 mmol) was dissolved in dichloromethane (5 mL), to which triethylamine (162 mg, 1.60 mmol) and methanesulfonyl chloride (183 mg, 1.60 mmol) were added dropwise sequentially at 0 ° C. After the reaction mixture was stirred at room temperature for 30 minutes, saturated aqueous sodium hydrogen carbonate solution was added, and the organic compound produced by dichloromethane was extracted, and then filtered through a pad of silica gel. The solvent was removed under reduced pressure to obtain the
1 H NMR (400 MHz, CDCl 3 ) δ 1.49-1.60 (m, 4H), 1.70-1.86 (m, 2H), 1.95-2.05 (m, 2H), 2.99-3.04 (d, 3H), 3.48-3.55 (m, 2H), 3.78-3.90 (m, 2H), 4.56-4.60 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 19.6, 25.4, 29.3, 30.6, 31.6, 37.3, 62.5, 62.8, 99.1
Example 3 Preparation of N- (1,1-dideuterium-3-toluenesulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (2c)
Step 1: Preparation of N- (1,1-dihydrogen-3-tetrahydropyranyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (10)
nor-β-CIT ( 4 , 100 mg, 0.27 mmol) was dissolved in anhydrous acetonitrile (5 mL) under argon gas, and then 1,1-dihydrogen-3- (tetrahydropyranyl) obtained in Preparation Example 2 Oxy) propyl methanesulfonate ( 9 , 78 mg, 0.32 mmol) and diisopropylethylamine (52 mg, 0.4 mmol) were added dropwise sequentially. The reaction mixture was heated at 80 ° C. for 5 hours and then the acetonitrile was removed under reduced pressure. Column chromatography with diethyl ether / n -hexane / triethylamine (40/60/1) gave the target compound N- (1,1-dihydrogen-3-tetrahydropyranyloxypropyl) as a colorless liquid. -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 10 , 98 mg, 71%) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.46-1.88 (m, 9H), 1.94-2.14 (m, 2H), 2.52 (tt, 1H, J = 12.4, 2.8 Hz), 2.84-2.89 (m, 1H ), 2.89-2.97 (m, 1H), 3.35-3.40 (m, 1H), 3.40-3.47 (m, 2H), 3.49 (d, 3H, J = 4.0 Hz), 3.66-3.70 (m, 1H), 3.70-3.80 (m, 1H), 3.80-3.90 (m, 1H), 4.50-4.56 (m, 1H), 7.00 (d, 2H, J = 7.2 Hz), 7.57 (d, 2H, J = 8.0 Hz) ; 13 C NMR (100 MHz, CDCl 3 ) δ 19.9, 20.0, 25.6, 25.95, 25.97, 26.2, 29.2, 29.3, 30.93, 30.94, 34.00, 34.01, 34.04, 34.05, 51.1, 51.2, 52.8, 52.9, 61.7, 61.8 , 62.5, 62.7, 62.8, 65.7, 65.9, 91.11, 91.12, 99.0, 99.3, 129.61, 129.62, 137.0, 143.29, 143.30, 171.96, 172.01
Step 2: Preparation of N- (1,1-dihydrogen-3-hydroxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (5b)
N- (1,1-dideuterium-3-tetrahydropyranyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane obtained in step 1 ( 10 , 60 mg, 0.12 mmol) was dissolved in methanol (2 mL), and then p -toluenesulfonic acid (27 mg, 0.14 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. Methanol was removed under reduced pressure, column chromatography was carried out with diethyl ether / triethylamine (97/3) to give the title compound N- (1,1-dihydrogen-3-hydroxypropyl) -2 as a colorless liquid. -β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 5b , 55 mg, 74%) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.47-1.75 (m, 1H), 1.78-1.80 (m, 4H), 1.98-2.18 (m, 2H), 2.51 (td, 1H, J = 12.8, 2.8 Hz ), 2.86-2.90 (m, 1H), 2.93-3.02 (m, 1H), 3.48 (s, 3H), 3.56-3.66 (m, 2H), 3.70-3.82 (m, 2H), 6.96 (d, 2H) , J = 8.4 Hz), 7.55 (d, 2H, J = 8.0 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 25.0, 26.5, 28.9, 33.7, 33.9, 51.5, 53.1, 59.3, 64.5, 64.8, 91.4, 129.5, 137.1, 142.3, 172.2
Step 3: Preparation of N- (1,1-dideuterium-3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (2c)
N- (1,1-dihydrogen-3-hydroxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane obtained in step 2 ( 5b , 50 mg, 0.12 mmol) was dissolved in anhydrous dichloromethane (1.2 mL) under argon gas, followed by anhydrous toluenesulfonate (83 mg, 0.26 mmol) and diisopropylethylamine (17 mg, 0.13 mmol). After stirring for 3 hours at room temperature, dichloromethane was removed under reduced pressure, and column chromatography was performed with diethyl ether / n -hexane / triethylamine (50/50/1) to give a colorless liquid N. -(1,1-dideuterium-3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 2c , 55 mg, 81%) was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.50-1.74 (m, 5H), 1.86-2.80 (m, 2H), 2.34 (td, 2H, J = 12.4, 2.8 Hz), 2.45 (s, 3H), 2.80-2.94 (m, 2H), 3.18-3.25 (m, 1H), 3.40 (s, 3H), 3.54-3.60 (m, 1H), 4.04-4.18 (m, 2H), 6.96 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.4 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 21.7, 25.8, 26.0, 28.4, 33.7, 33.8, 51.0, 52.5, 61.4, 62.9, 68.9, 91.0, 125.9, 127.9, 128.6, 128.9, 129.4, 129.8, 133.2, 136.8 , 137.5, 142.9, 144.6, 171.7
Experimental Example 2 N- (1,1-dideuterium-3-toluenesulfonyloxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (2c) and its Reversible Reaction with Azetidinium Salts (1c)
Step 1: Azetidinium salt of N- (1,1-dideuterium-3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane (1c) Manufacture
N- (1,1-dideuterium-3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane obtained in Example 3 ( 2c , 55 mg) , 0.1 mmol) was dissolved in acetonitrile (8 mL), heated at 70 ° C. for 30 minutes, and then acetonitrile was removed under reduced pressure. After dissolving in a small amount of dichloromethane, excess diethyl ether was added and centrifuged to give a white solid target compound azetidinium salt ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl ) -2 '-(methoxycarbonyl) spiro [2,2-dihydrogenazetidine-1,8'-bicyclo [3.2.1] octane] -1- 윰 toluenesulfonate ( 1c , 53 mg, 96%).
1 H NMR (400 MHz, CDCl 3 ) δ 1.82-2.00 (m, 2H), 2.04-2.14 (m, 1H), 2.32 (s, 3H), 2.34-2.46 (m, 3H), 2.67-2.80 (m , 2H), 3.12-3.25 (m, 2H), 3.47 (s, 3H), 4.18-4.26 (td, 1H, J = 10.0, 4.0 Hz), 4.46-4.62 (m, 2H), 4.70-4.78 (m , 1H), 6.92 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.75 (d, 2H, J = 8.0 Hz ); 13 C NMR (100 MHz, CDCl 3 ) δ 14.7, 21.4, 23.1, 24.7, 27.1, 31.3, 48.8, 52.5, 56.3, 65.4, 68.2, 92.4, 126.0, 128.7, 129.1, 137.5, 138.9, 139.3, 144.2, 170.4
Step 2: Azetidinium Of salt (1c) Ring opening reaction
Azetidinium salt obtained in step 1 ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl) -2'-(methoxycarbonyl) spiro [2,2-dihydrogen Azetidine-1,8′-bicyclo [3.2.1] octane] -1- 윰 toluenesulfonate ( 1c , 40 mg) was dissolved in benzene (10 mL), heated at 70 ° C. for 1 hour, benzene was removed under reduced pressure, and NMR spectrum was obtained.
1 H NMR (400 MHz, CDCl 3 ) δ 1.50-1.76 (m, 5H), 1.86-2.10 (m, 2H), 2.22-2.28 (m, 1H), 2.30-2.40 (m, 1H), 2.45 (s , 3H), 2.78-2.94 (m, 2H), 3.16-3.26 (m, 1H), 3.40 (s, 3H), 3.53-3.60 (m, 1H), 4.04-4.18 (m, 1H), 6.96 (d , 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3 ) δ 21.8, 26.0, 26.1, 28.5, 33.8, 33.9, 49.4, 51.1, 52.7, 52.8, 61.5, 61.6, 63.03, 63.07, 69.0, 91.2, 126.1, 128.0, 128.7, 129.0 , 129.5, 130.0, 137.0, 137.6, 143.1, 144.7, 171.8
In Experimental Example 2, an azetidinium salt ( 1'R, 2'S, 3'S, 5'S ) -3 '-(4-iodophenyl) -2'-(methoxycarbonyl) spiro, which is the target compound of step 1 [2,2-dideuterium azetidine-1,8'-bicyclo [3.2.1] octane] -1- 윰 toluenesulfonate ( 1c ) shows an NMR spectrum indicating that only one of the two expected compounds is produced. The ring opening reaction was performed in a non-polar benzene solvent in
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N- (3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane ( 2b ) and azetidinium obtained in step 2-2 of Preparation Example 1 The nucleophilic fluorination reaction with salt ( 1b ) was carried out. At this time, the precursor compounds 2b and 1b were used each 5 mg (0.0086 mmol), the reaction solvent was used t -butanol (1 mL). Tetra- n -butylammonium fluoride (TBAF) was used 5 mg (0.0172 mmol) each, and reacted at 80 ° C. for 30 minutes.
t - Butanol In solvent Nucleophilic Substitution reaction
Using t -butanol as a solvent, the reaction mixture was taken at 5, 10, 15, 20 and 30 minutes and analyzed by HPLC, and the results are shown in Table 3 below and FIGS. 5 and 6.
As shown in Table 3, in the case of N- (3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane represented by Formula 2b , for 30 minutes It can be seen that the reaction takes place slowly, and after 30 minutes, the product represented by the formula (3) is obtained at 27.2%, whereas the adduct of the formula (11) is rapidly formed at the beginning of the reaction, reaching 68.2% after 30 minutes. .
In addition, in the case of an azetidinium salt of N- (3-toluenesulfonoxypropyl) -2-β-carbomethoxy-3-β- (4-iodophenyl) tropane represented by the formula (1b) according to the present invention, The reaction was terminated in 5 minutes and 51.2% of product was obtained.
Thus, it was found that tertiary alcohol solvents such as t -butanol were effective for nucleophilic fluorination reactions using the azetidinium salt precursors of the present invention, and N- (3-toluenesulfonoxypropyl) -2-β-carbome Compared to the nucleophilic fluorination reaction of the oxy-3-β- (4-iodophenyl) tropane ( 2b ) precursor, the azetidinium salt represented by the general formula ( 1b ) according to the present invention is 7 times faster and about 2 times faster. It can be seen that the high yield.
Claims (16)
[Formula 1]
(In Formula 1, R is methyl, trifluoromethyl, phenyl, toluenyl, 4-bromophenyl, or 4-nitrophenyl)
[Formula 1]
(In Formula 1, R is methyl, trifluoromethyl, phenyl, toluenyl, 4-bromophenyl, or 4-nitrophenyl)
[Reaction Scheme 1]
(In Scheme 1, R is methyl, trifluoromethyl, phenyl, toluenyl, 4-bromophenyl, or 4-nitrophenyl)
[Reaction Scheme 2]
(In Scheme 2, R is methyl, trifluoromethyl, phenyl, toluenyl, 4-bromophenyl, or 4-nitrophenyl)
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US20100113763A1 (en) | 2004-12-15 | 2010-05-06 | Futurechem Co., Ltd. | Method for preparation of organofluoro compounds in alcohol solvents |
US20100256389A1 (en) | 2007-12-07 | 2010-10-07 | Franziska Wagner | Method for producing precursors for l-2- [18f] fluorophenylalanine and 6- [18f] fluoro-l--meta-tyrosine and the alpha-methylated derivatives thereof, precursor, and method for producing l-2- [18f] fluorophenylalanine and 6- [18f] fluoro-l-meta-tyrosine and the alpha-methylated derivatives from the precursor |
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US20100256389A1 (en) | 2007-12-07 | 2010-10-07 | Franziska Wagner | Method for producing precursors for l-2- [18f] fluorophenylalanine and 6- [18f] fluoro-l--meta-tyrosine and the alpha-methylated derivatives thereof, precursor, and method for producing l-2- [18f] fluorophenylalanine and 6- [18f] fluoro-l-meta-tyrosine and the alpha-methylated derivatives from the precursor |
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