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Direct synthesis of 18f-fluoromethoxy compounds for pet imaging and the provision of new precursors for direct radiosynthesis of protected derivatives of o-([18f]fluoromethyl) tyrosine

A compound, methyl technology, applied in the field of direct synthesis

Inactive Publication Date: 2014-06-11
PIRAMAL IMAGING SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

None of these documents teach the use of ON-active groups as leaving groups for the synthesis of fluoromethoxy-groups

Method used

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  • Direct synthesis of 18f-fluoromethoxy compounds for pet imaging and the provision of new precursors for direct radiosynthesis of protected derivatives of o-([18f]fluoromethyl) tyrosine
  • Direct synthesis of 18f-fluoromethoxy compounds for pet imaging and the provision of new precursors for direct radiosynthesis of protected derivatives of o-([18f]fluoromethyl) tyrosine
  • Direct synthesis of 18f-fluoromethoxy compounds for pet imaging and the provision of new precursors for direct radiosynthesis of protected derivatives of o-([18f]fluoromethyl) tyrosine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0853]

[0854] N-(tert-butoxycarbonyl)-D-tyrosine tert-butyl ester 3-1-1

[0855] To a stirred solution of D-tert-butyl tyrosine (47.46 g, 200 mmol) in dichloromethane (600 ml) and N,N-dimethylformamide (60 ml) was added triethylamine (22 g, 220 mmol) and di Di-tert-butyl carbonate (43, 65 g, 200 mmol). The mixture was stirred at room temperature for 2 hours, then washed with 1N aqueous hydrochloric acid (3 x 100ml), saturated sodium bicarbonate (100ml), brine (100ml), dried (magnesium sulfate) and concentrated to give 3-1-1 as a bright yellow oil , let it stand to solidify. Yield 64g (95%).

[0856] MS (CI, NH 3 ):m / z=355(M+NH 4 ),388(M+H),399(M+NH 4 -C 4 h 8 ),382(M+H-C 4 h 8 ),238(M+H-C 4 h 8 -CO 2 ).

[0857] 1 H-NMR (400MHz, CD 2 Cl 2 ):δ=7.00(d,J=8.3Hz,2H,Ar),6.74(d,J=8.1Hz,2H,Ar),5.31(d,J=8.1Hz,1H,NH),4.33(mc, 1H, 2-H), 2.94 (mc, 2H, 3-H), 1.41ppm (s, 18H, 1-tBu, 2-tBu).

[0858] 13 C-NMR (100MHz, CD 2 Cl 2 ): δ (ppm) 171.13 (C1), 155.59 (br., 2...

Embodiment 2

[0895]

[0896] N,O-bis(tert-butoxycarbonyl)-D-tyrosine 3-2-1

[0897]18.1 g (100.0 mmol) of D-tyrosine were suspended in 250 ml of water and a solution of 65.4 g (300.0 mmol) of di-tert-butyl dicarbonate in 150 ml of 2-propanol was added. The pH was adjusted to 11.5-12 by repeated additions of sodium hydroxide (32% in water). The reaction was heated slowly to about 37°C and brought to 20°C by cooling. Then 250 ml of water were added and the mixture was extracted with ether. The combined organic phases were washed with water and dried over sodium sulfate. Evaporation of the solvent gave a sticky residue which was dissolved in ethyl acetate. The solution was filtered and hexane was added. White crystals formed by evaporation and dried under vacuum at 30°C. Yield was 39.1 g (>100%).

[0898] alpha D =-27.9(c=1, dioxane).

[0899] MS (ESI + ):m / e=785(2M+Na + ),763(2M+H + ),663(2M+H + -C 4 h 8 -CO 2 ), 404 (M+Na + ).

[0900] MS(ESI-):m / e=761(2M-H + ),661(2M-H...

Embodiment 3

[0980]

[0981] N,O-bis(tert-butoxycarbonyl)-D-tyrosine-2,4-dimethoxybenzyl ester 3-3-1

[0982] Dissolve 5.0 g (13.1 mmol) of 3-2-1 and 160 mg (1.31 mmol) of 4-(dimethylamino)pyridine in 30 ml of dichloromethane (previously passed Molecular sieve drying). Add 2.87g (17.0mmol) 2,4-dimethoxybenzyl alcohol and 3.27g (17.0mmol) N-ethyl-N'-3-dimethylaminopropyl carbodiimide hydrochloride, and at room temperature The mixture was stirred overnight. Ethyl acetate was added and insolubles were filtered off. The filtrate was concentrated in vacuo. Using 500 g of silica gel and a step gradient (1 L hexane, hexane / ethyl acetate 9:1, hexane / ethyl acetate 8:2, hexane / ethyl acetate 7:3, hexane / ethyl acetate 6:4) yielded 2.15 g (31%) of 3-3-1. (Smaller scale reaction gave 49-55% yield).

[0983] MS (ESI + ):m / e=549(M+H + +OH),532(M+H + ),151(C 9 h 11 o 2 + ).

[0984] 1 H NMR(chloroform-d,400MHz):δ(ppm)7.19(d,J=9.1Hz,2H,Dmb H-7),6.98-7.10(m,4H,Dmb H6,H-4,Tyr H-4 / 8),6.42-...

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Abstract

The invention describes novel direct synthesis methods for converting a precursor into a PET-tracer with a 18F-fluoromethoxy-group. The invention is also directed to novel and stable precursors for the direct radiosynthesis of protected derivatives of O- ([18F]Fluoromethyl) tyrosines.

Description

field of invention [0001] The present invention describes methods for converting precursors into 18 Novel direct synthesis of F-fluoromethoxy PET-tracers. The present invention also describes the method for direct radiosynthesis of O-([ 18 Novel stable precursors of protected derivatives of F]fluoromethyl)tyrosine, and methods for obtaining those compounds. Background technique [0002] For some time, fluoromethoxy has been used to introduce fluorine into compounds of biological interest. It has the advantage of being very similar in steric requirements to methoxy. Fluoromethoxy can be used in place of methoxy in biologically active compounds without loss of affinity to the target of interest and is therefore very commonly used. Although formally a formal derivative, fluoromethoxy is a very stable group in many molecules. Especially as a substituent on an aromatic ring, substitution of methoxy by fluoromethoxy leads to chemically stable compounds. However, the stabilit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/04C07D249/18C07D471/04
CPCC07D471/04C07D249/04C07D249/18A61K51/0453A61K51/0455C07C227/16C07C229/36C07C269/06C07C271/22
Inventor 托马斯·布鲁姆贝基斯·格雷厄姆马丁·克鲁格尔
Owner PIRAMAL IMAGING SA
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