Carbon-11 labeled Larotrectinib compound and preparation method thereof

A compound and labeling technology, applied in organic chemistry, radioactive carriers, etc., can solve the problems of time-consuming and infeasible, and achieve the effects of shortening the reaction time, simple and easy operation steps, and less usage

Pending Publication Date: 2022-04-05
SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned two-step reaction of this method still takes as long as 6 hours, which is also unacceptable and infeasible for obtaining carbon-11 markers with a short half-life

Method used

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  • Carbon-11 labeled Larotrectinib compound and preparation method thereof
  • Carbon-11 labeled Larotrectinib compound and preparation method thereof
  • Carbon-11 labeled Larotrectinib compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～5

[0148]

[0149] step one:[ 11 Synthesis of C]-3-(isocyanato)pyrazolo[1,5-a]pyrimidine analogue intermediate (compound 4)

[0150]

[0151] 1 milliliter of V-type reaction bottle, after nitrogen flow (10ml / min) purging 5 minutes, add 100 μ L acetonitrile, 5 μ L BEMP, 100 μ g compound 1, the [ 11 CO 2 ]CO 2 Under the purging of nitrogen flow (10mL / min), pass through the acetonitrile solution above, and pass through the small radiation detector at the proximal end, measure the radioactivity captured by the solution until it reaches the peak value. After reacting for 1 min, add 100 μl of freshly prepared POCl 3 (0.2% v / v) acetonitrile solution, reacted for 30 seconds, sampled and analyzed to obtain compound 4, which was directly used in the next reaction without purification.

[0152] Step two, [ 11 Preparation of C]-3-R-Larotrectinib Compound

[0153]

[0154] Add 100 μL of compound 2 (0.2 mg) in acetonitrile solution to the reaction mixture in step 1. After reacti...

Embodiment 6

[0160] step one:[ 11 Synthesis of C]-3-(isocyanato)pyrazolo[1,5-a]pyrimidine analogue intermediate (compound 4)

[0161] Same as Step 1 of Example 1.

[0162] Step two, [ 11 Preparation of C]-Larotrectinib Compound

[0163]

[0164] In the reaction mixture in step 1, add 100 μl of (S)-3-pyrrolidinol (0.15 mg) in acetonitrile solution, react for 1 minute, take a sample for analysis and detection, TLC traces that the labeled precursor compound 4 basically disappears, radioactive TLC traces the reaction Mixture sampling (1-2μL) was tested to have [ 11 C] - Larotrectinib labeled product. The reaction was quenched with 750 μl of ethanol / water (1 / 1, v / v). After the mixture was separated and purified by preparative HPLC (the specific process was the same as in Example 1), the eluate of the target product was collected and concentrated to dryness in vacuum at 70° C. ,get[ 11 C] - Larotrectinib compound.

Embodiment 7～12

[0166]

[0167] step one,[ 11 C]COF 2 Synthesis;

[0168]

[0169] cyclotron nuclear reaction 14 N(p,α) 11 C produces [ 11 C]CO 2 (3–4GBq), successively passed through a hot molybdenum target (875°C), a sodium hydroxide absorption bottle, and a stainless steel Erlenmeyer bottle cooled by liquid nitrogen containing 0.4g AgF 2 , the whole process takes 11-12 minutes to complete, [ 11 C]COF 2 Radiochemical yield (RCY) 71 + / - 2%. Under the condition of 5mL / min helium flow rate, 0.4g of AgF 2 can almost quantitatively [ 11 C] CO into [ 11 C]COF 2 . It was not detected in the NaOH system [ 11 C]COF 2 or[ 11 C]CO 2 , AgF 2 It can also be recycled.

[0170] References, Preparation [ 11 C] Fluorophosgene.Jimmy E.Jakobsson et al.,(2020).[11C]Carbonyldifluoride-a new and highly efficient[11C]carbonyl group transferagent.Angew.Chem.Int.Ed.,DOI: 10.1002 / anie. 201915414

[0171] Step two, [ 11 Preparation of C]-3-R-Larotrectinib Compound

[0172]

[0173] [ ...

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Abstract

The invention discloses a carbon-11 labeled Larotrectinib compound, the chemical structural formula of the compound is as follows: the compound can be obtained by mixing and reacting with carbon-11 labeled fluorophosgene, or the compound can be obtained by introducing carbon-11 labeled carbon dioxide into a solution containing BEMP and then adding POCl3 after the reaction is finished, and the compound is obtained by reacting with the BEMP and the POCl3. Compared with the prior art, the synthesis of the short half-life period carbon-11 labeled Larotrectinib is successfully realized, the radiochemical purity of the marker is high, and the short half-life period carbon-11 labeled Larotrectinib is suitable for clinical requirements on the short half-life period carbon-11 labeled Larotrectinib.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, especially in vivo imaging agents of Trk receptor subtypes in refractory solid tumors, in particular to a radiocarbon based novel inhibitor of tyrosine receptor kinase (TRK), Larotrectinib compound [ 11 C]-Larotrectinib and its preparation method. Background technique [0002] Larotrectinib was developed by Loxo Oncology as a broad-spectrum tumor drug for all patients with tumors expressing tropomyosin receptor kinase (TRK), rather than targeting tumors at a certain anatomical location. This small molecule inhibitor of TRK has strong selectivity for TRK. By inhibiting the TRK signaling pathway, larotrectinib can inhibit the growth of tumors. Larotrectinib is an oral potent TRK inhibitor with consistent and durable antitumor activity in TRK fusion tumors, applicable to a wide range of patient ages and tumor types, its indications are distributed in 13 different tumor types, and has a good ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K51/04
Inventor 黄钢李斌李玥
Owner SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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