AU2019400110B2 - Radioactive fluorine-labeled Larotrectinib compound and preparation method therefor - Google Patents
Radioactive fluorine-labeled Larotrectinib compound and preparation method therefor Download PDFInfo
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- AU2019400110B2 AU2019400110B2 AU2019400110A AU2019400110A AU2019400110B2 AU 2019400110 B2 AU2019400110 B2 AU 2019400110B2 AU 2019400110 A AU2019400110 A AU 2019400110A AU 2019400110 A AU2019400110 A AU 2019400110A AU 2019400110 B2 AU2019400110 B2 AU 2019400110B2
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- 229950003970 larotrectinib Drugs 0.000 title claims abstract description 1078
- 238000002360 preparation method Methods 0.000 title claims abstract description 216
- -1 Larotrectinib compound Chemical class 0.000 title claims abstract description 45
- 230000002285 radioactive effect Effects 0.000 title claims abstract description 30
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 16
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000011737 fluorine Substances 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 343
- 239000000047 product Substances 0.000 claims description 260
- 239000000243 solution Substances 0.000 claims description 259
- 239000002243 precursor Substances 0.000 claims description 195
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 171
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 161
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 107
- 238000000034 method Methods 0.000 claims description 101
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- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 claims description 64
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000001972 liquid chromatography-electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 1
- MCPQOHJPXRJCEN-UHFFFAOYSA-N methyl 4-(5-fluoro-2-iodophenyl)-4,4-dimethoxybutanoate Chemical compound FC=1C=CC(=C(C1)C(CCC(=O)OC)(OC)OC)I MCPQOHJPXRJCEN-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- DNBWGFKLIBQQSL-UHFFFAOYSA-N n-methyl-1-pyridin-4-ylmethanamine Chemical compound CNCC1=CC=NC=C1 DNBWGFKLIBQQSL-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010002164 tyrosine receptor Proteins 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/02—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 two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
A radioactive fluorine-labeled Larotrectinib compound and a preparation method therefor, particularly, an in-vivo imaging agent of a Trk receptor subtype in a refractory solid tumor. Provided are a radioactive fluorine compound
Description
[0001] 1. Technical Field
[0002] The invention relates to the field of chemical drug synthesis, especially to
an in vivo imaging agent for Trk receptor subtype in refractory solid tumors, and more
particularly to a radioactive fluoride 18F-Larotrectinib based on a novel tyrosine receptor
kinase (TRK) inhibitor Larotrectinib and its 18F-Larotrectinib analogs, and more
particularly to a preparation method of the radioactive 18F-labeled compound
18F-Larotrectinib and 18F-Larotrectinib analogs based on Larotrectinib and its analogs.
[0003] 2. Description of Related Art
[0004] Larotrectinib was developed by Loxo Oncology. As a broad-spectrum
tumor drug, it is used for all tumor patients that express (TRK). This small-molecule TRK
inhibitor is highly selective for TRK. By inhibiting the TRK signaling pathway,
larotrectinib can inhibit tumor growth. Larotrectinib is a potent oral TRK inhibitor with
consistent and long-lasting anti-tumor activity in TRK fusion tumors. It is applicable to a
wide range of patient ages and tumor types and its indications are distributed in 13
different tumor types.Larotrectinib has good tolerance, is effective against a variety of
solid tumors in adults and children, including salivary, infantile fibrosarcoma, lung cancer,
thyroid cancer, colon cancer, melanoma (melanoma), cholangio cancer, GISTs, breast
cancer, and various sarcoma cancers. The US FDA (http://www.chemdrug.com/article/I1/)
has granted orphan drug designation and breakthrough drug designation to larotrectinib.c
Larotrectinib is expected to become the first therapeutic drug to be developed and
approved simultaneously for adults and children, and it is the first tumor-targeted
therapeutic drug that spans all traditionally defined tumor types and molecular meanings.
The structure of Larotrectinib is as follows:
- N' OH F~Q HN Larotrectinib O
[0005] However, at present, for the distribution of drug molecules in the body and
the evaluation of curative effect, the positron-emitting radiopharmaceutical
18F-deoxyglucose (18F-FDG) is usually used to indirectly evaluate the curative effect of
the drug on tumors and related diseases. Moreover, the positron-emitting
radiopharmaceutical 18F-deoxyglucose (18F-FDG) also has high FDG absorption in
non-tumor tissues and inflammatory cell components, which may cause false positive
results in tumor diagnosis due to inflammation when FDG is used in tumor imaging.
Therefore, how to on line trace the distribution of Larotrectinib in humans or animals and
the status in solid tumors in vivo, intuitively determine the physiological functions of
Larotrectinib in tumors, and evaluate its curative effect and its healing effect is a pressing
problem.
[0006] PET (Positron emission tomography) is a non-immersive imaging
technology that can realize the visualization and quantitative evaluation of the
physiological and biochemical functions of drug molecules and the pharmacological
process at the molecular level in vivo. As a small molecule inhibitor for tropomyosin
receptor kinase (TRK), Larotrectinib molecule is highly selective for TRK and can be used
as a PET imaging molecule to accurately locate Larotrectinib molecules in vivo to
evaluate tumor conditions, realize online tracing of Larotrectinib molecules in animals or
humans and the status in solid tumors, intuitively determine the physiological function and
pharmacological process of Larotrectinib in animals, humans and tumors, and evaluate its
curative effect and its healing effect. There is no more effective technical means at present.
[0007] The objective of the invention is to provide a [ 18F]-labeled Larotrectinib
compound and a preparation method thereof in order to overcome the above-mentioned
defects in the prior art.
[0008] The objective of the invention can be reached by the following technical
solutions: A [ 18F]-labeled Larotrectinib compound, including a [ 18F]-Larotrectinib
compound having the following structural formula and its analogs:
F 18F
18F (R) N F ( N HN NNHN 8 F F2arorecin F N- .' 1 0 2 0 18 F-2-Larotrectinib 18 F-5-Larotrectinib
18F-2-Larotrectinib 18F-5-Larotrectinib
18 F
18F 2( 1(2OH R1(2) NN OH
>R) N (R) HN N HN
3 0 4 18 18 F-2-Larotrectinib analogues F-5-Larotrectinib analogues
18F-2-Larotrectinib analogues 18F-5-Larotrectinib analogues
[0009] A preparation method of the [ 18F]-labeled Larotrectinib compound includes
the following steps:
[0010] step 1: hydroxyl protection: protection of the active hydroxyl group of the
iodo-Larotrectinib analog precursor (I-Larotrectinib);
[0011] step 2: preparation of a labeled precursor: carrying out iodine activation on
Jodo-Larotrectinib analogue precursor (I-Larotrectinib) to prepare a trifluoroacetic acid
I-Larotrectinib analogue, and then causing the trifluoroacetic acid I-Larotrectinib analogue
to react with an adamantane-substituted auxiliary acid to prepare a labeled precursor: hydroxy-producted spirocyclic hypervalent I(III)-Larotrectinib analogue ; and
[0012] step 3: preparation of 18F-labeled product: carrying out substitution reaction
of the labeled precursor with a 18F radioactive source to prepare hydroxyl-protected
18F-Larotrectinib and synthesize a 18F-Larotrectinib analog, and then carrying out
deprotection to obtain 1 8 F-Larotrectinib and a1 8 F-Larotrectinib analogue.
[0013] The synthesis route of 18F-2-Larotrectinib is as follows:
OH N'.N OOCC 6 H5 NN
NaN N
C 2 1H 22FIN 60 2: 536.35 C 21H 26FING0 3:640.46 I - 2-Larotrectinib I - Bz-2-Larotrectinib
F NN OOCC6 H 5 0 ' N OOCC 6 H5 F 3 CCOO- 1 H FF3CCO N y He
C3 2 H 28 F7 N 6 O7 :868.50 H C41H42 FINOO 7 :876.72 I - Bz-TfAc-2-Larotrectinib |(lll)-SPAd - Bz-2-Larotrectinib
;; N,-N OH F P N -N OOCC6H5 18 18 F N F N
OQ 0 NN~ 6N 0 OH 18 8 C 2 8 H2 6 F FN6 0 3: 531.55 C2 1H 2 2 F' FN 6 0 2 : 427.45 18 18 F -Bz-2-Larotrectinib F - 2-Larotrectinib
[0014] The synthesis route of 18F-5-Larotrectinib is the same as that of
18F-2-Larotrectinib except that the substitution of I in the iodo-Larotrectinib analogue
precursor (I-Larotrectinib) in the raw material is 5-position substitution. The specific
synthesis route is as follows:
F NF HN -if N
C 21H22FIN 602 : 536.35 C28H 26FIN 60 3:640.46 1 -5- Larotrectinib I - Bz-5-Larotrectinib
FCCOO OHO '-OOCCF 3 O H
N.-- OOCCH OCC 6 5
3 HN N FN6 C 32H 28FyN 607:868.50 4 1 - Bz-TfAc-5-Larotrectinib C 411- 42 FIN 6 07:876.72 I(Ill)-SPIAd - Bz-5-Larotrectinib
18 'OF F
NN OH F/ N-N OOCC6H' F F
FN N1N Ff N
O 0 18 18 C 2gH 26F FN60 3: 531.55 C21H 22F FN 602 : 427.45 18 18 F -Bz-5-Larotrectinib F -5-Larotrectinib
[0015] The iodo-Larotrectinib analogue precursor in step 1 has the following
structural formula:
R2 N'N OR3
[0016] in the above formula, RI and R2 each independently represent a phenyl
substituent, RI and R2 are each independently selected from group consisting of H,
halogen, hydroxyl, nitro, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 10 carbon atoms, aryl with 6 to 10 carbon atoms, heterocycloalkyl with 4 to 10 carbon atoms, and heteroaryl with 6 to 10 carbon atoms; RI and R2 each independently form a group with R3;
[0017] in the above formula, R3 specifically represents H; the protection of the
active hydroxyl functional group means that through esterification or etherification, R3 is
substituted with the following functional groups to protect the active hydroxyl, and the
substituted functional groups include trimethylsiloxane (TMS), tert-butyldimethylsiloxane
(TBDMS), triethylsiloxane (TES), tert-butyldiphenylsiloxane (TBDPS), methyl ether
(Me), benzyl ether (Bn), trityl ether (Tr), p-methoxytrityl ether (MMT), dimethoxytrityl
ether (DMT), tert-butyl ether ( tBu), methoxy methyl ether (MOM), 2-methoxy ethoxy
methyl ether (MEM), methylthio methyl ether (MTM), benzyloxy methyl ether (BOM),
p-methoxybenzyl ether (PMB), p-methoxybenzyloxy methyl ether (PMBOM),
3,4-dimethoxybenzyl ether (DMB), tetrahydropyran ether (THP), methoxycarbonyl (Moc),
ethoxycarbonyl (Eoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),
9-fluorenylmethoxycarbonyl (Fmoc), acetyl (Ac), trifluoroacetyl (TfAc), chloroacetyl
Base (CAc), dichloroacetyl (DCAc), benzoyl (Bz), pivaloyl (Pv), methanesulfonyl (Ms),
benzylsulfonyl (Bs), allylsulfonyl (Bs), allyl Alkyloxycarbonyl (Als), allyloxycarbonyl,
alkanoyl with 1 to 16 carbon atoms,enoyl with 2 to 16 carbon atoms, alkynyl with 3 to 6
carbon atoms, cycloalkyl with 4 to 10 carbon atoms, aroyl with 7 to 16 carbon atoms, and
heterocycloalkanoyl with 4 to 10 carbon atoms; optionally, the substituted functional
groups can be substituted by 1, 2, 3 or 4 independent R3 groups, the alkanoyl is preferably
acetyl, and the aroyl is preferably benzoyl; the substituted functional groups can be
optionally substituted by 1, 2, 3 or 4 independent R3 groups, and the substituted alkanoyl
is pivaloyl or phenylacetyl.
[0018] The preparation of trifluoroacetic acid iodo-Larotrectinib analogue in step 2
is to cause the iodo-Larotrectinib analog precursor (I-Larotrectinib) with protected active hydroxyl prepared in step 1 to react with trifluoroacetic acid or trifluoroacetic anhydride, an organic solvent and an oxidant so that I is activated by trifluoroacetate;
[0019] the organic solvent includes one or more of chloroform, dichloromethane,
acetonitrile, acetone, and tert-butanol peroxide;
[0020] the oxidant includes a urea-hydrogen peroxide complex, Oxone,
2,2,6,6-tetramethylpiperidine-oxideormCPBA.
[0021] The adamantane-substituted auxiliary acid in step 2 is SPIAd, and the
conditions for the reaction of SPIAd with trifluoroacetic acid iodo-Larotrectinib analog are
as follows: SPIAd is mixed with one or more of sodium carbonate solution, MeCN,
NaHCO3 and acetone at 0°C, and the pH of the mixed solution is controlled to be 8 to 10,
and the mixed solution reacts with the trifluoroacetic acid iodo-Larotrectinib analogue at
°C while continuously stirring for 1 hour to 10 hours, thus obtaining the labeled
precursor.
[0022] The 18F radioactive source in step 3 is obtained by the following method:
[0023] (1) preparation of [ 18F] fluoride target water: producing [1 8F] fluoride target
water by 1 80(p,n) 18F nuclear reaction, and delivering the [ 18F] fluoride target water to a
sterile lead-protected hot cell of 180-enriched water by nitrogen pressure, wherein [ 18F]
fluoride target water produced by this method is usually further diluted with Milli-Q
(Millipore ultrapure water instrument) ultra-purified water to obtain 1-3mCi/ml 1[ 8F]
fluoride target water liquid before being used in research.
[0024] (2) enrichment of [ 18F] fluoride by QMA anion exchange solid phase
extraction cartridge (QMA): causing an aliquot of the target water containing an
appropriate amount of [ 18F] fluoride to slowly pass through the anion exchange solid
phase extraction cartridge (QMA) under a nitrogen flow, wherein the anion exchange solid
phase extraction cartridge (QMA) is pre-activated by washing with NaHCO 3(aq)(8.4% lmL) and water (20 mL, until the pH indicator shows neutrality); enriching the 1[ 8 F] fluoride on the QMA anion exchange solid phase extraction cartridge (QMA), and removing 180 and other impurities by separation and elution, thus obtaining [ 18F] fluorine source for the [ 18F] fluoride QMA anion exchange solid phase extraction cartridge
[0025] (3) eluting the [ 18F] fluoride enriched on the QMA anion exchange solid
phase extraction cartridge (QMA) to obtain a quaternary ammonium salt or inorganic salt
solution of [ 18F] fluoride; washing the [ 18F] fluoride enriched on QMA anion exchange
solid phase extraction cartridge (QMA) with a washing solution obtained by dissolving an
organic or inorganic base (for example, a certain amount of tetraethylammonium
bicarbonate, e.g., 8mg) in acetonitrile and water (lmL, v/v 7:3) or acetonitrile (mL) or
methanol (lmL) or ethanol (lmL) and eluting the [ 18F] fluoride into a V-shaped flask
sealed with a Teflon-lined diaphragm, thus obtaining an acetonitrile aqueous solution or
an acetonitrile or methanol solution of the organic or inorganic salt of [ 18F] fluoride; and
[0026] (4) preparation of a dry quaternary ammonium salt or inorganic salt of [1 8F]
fluoride: heating the V-shaped flask containing the acetonitrile aqueous solution or
acetonitrile or methanol or ethanol solution of the organic or inorganic salt of [ 18F]
fluoride and sealed with a Teflon-lined diaphragm to 95 C to 110 'C, and at the same
time drying nitrogen gas by passing through a P 20-DrieriteTM column to blow the
V-shaped flask, and then discharging the exhaust gas through the vented flask; when no
liquid is seen in the flask, taking the flask out of the hot bath, dosing anhydrous
acetonitrile (1 mL) in the flask, and heating the flask again until the flask is dry; repeating
this step another three times; then, cooling the flask at room temperature under nitrogen
flow, thus obtaining a dry organic or inorganic salt of [ 18F] fluoride, such as
[18F]KF/K2C03/K2.2.2, [18F]KF/K 2C 20 4/K2.2. 2, [' 8F]KF/KOTf, [' 8F]Et 4NF, [' 8F]Et 4NHCO 3 ,
[ 18F]Et4NOMs, and [ 18F]Et4NOTf; its radioactive [ 18F] fluoride recovery rate varies depending on the elution process used.
[0027] The substitution reaction between the labeled precursor and the 18F
radioactive source in Step 3: dosing a solvent in the V-shaped flask containing the dry
organic or inorganic salt of [ 18F] fluoride to re-dissolve the dry organic or inorganic salt,
and then dosing the labeled precursor to take reaction, thus obtaining a crude reaction
solution of undeprotected labeled product [ 18F]-Larotrectinib.
[0028] Deprotection in step 3 is implemented by the following method: dosing or
not dosing a certain amount of organic base or inorganic base or organic acid or inorganic
acid in the crude reaction solution of undeprotected labeled product [ 18F]-Larotrectinib,
and removing the hydroxyl protecting group by heating, thus obtaining a crude reaction
solution of labeled product [ 18F]-Larotrectinib.
[0029] The crude reaction solution of labeled product [ 18F]-Larotrectinib is
separated and purified by the following method: purifying the crude reaction solution of
labeled product [ 18F]-Larotrectinib by semi-preparative HPLC or Waters Sep-Pak C-18
cartridge, and rinsing the purified product with a solvent into a sterile vacuum flask, blow
drying with nitrogen at 60 °C for 20 minutes, and reconstituting a solution with brine,
wherein the obtain solution includes 100ul of 25% Vitamin C aqueous solution and 100ul
of 20% Tween 80 ethanol solution is a labeled product [ 18F]-2-Larotrectinib injection.The
labeled product [18F]-Larotrectinib injection is analyzed and identified by the following
method:
[0030] The identity and purity (radiochemical purity and chemical purity) of the
product are determined by radio-HPLC (60:40 CH 3CN:H 20+0.IN ammonium formate,
Phenomenex Luna C 1 8, 250 x 4.6 mm, 5 m, UV at 254 nm; CH 3 CN/0.1 M NH4•HCO 2
(aq) (v/v, 7/3), flow rate: 1.0 mL/min) and radio-TLC (EtOAc + 0-5% EtOH). The product
had the radiochemical purity and chemical purity of greater than 90% to 99%. The
radiochemical yield is determined as the percentage of radioactivity of the labeled precursor dosed to the DMF-diluted [1 8 F]Et 4 NHCO3 and separated as the final product from the amount of activity in the V-shaped reaction flask, without attenuation correction.
The radiochemical yield was 20 to 45.3 (without attenuation correction), the
radiochemical purity was greater than 99%, and the specific activity was 2.56 Ci/mol to
18 Ci/umol.
[0031] Compared with the prior art, the invention has the following beneficial
technical effects:
[0032] (1) The invention provides a 18F-labeled compound 1 8F-Larotrectinib and
its analogs, and further provides a preparation method of the 18F-labeled compound and its
analogs; that is, the 1 8F-labeled compound 18F-Larotrcetinib is prepared by the trivalent
iodine substitution method. The reaction speed is high, the reaction conditions are
relatively mild, the operation is simple, the reaction time is short, the post-processing is
simple, and the carrier-free radiolabeled compound can be prepared with a high
radiochemical purity.
[0033] (2) The invention provides a 18F-labeled compound 1 8F-Larotrectinib and
its analogues having the characteristics of emitting positrons; with the help of PET-CT
positron emission tomography technology, the distribution of the Larotrectinib compound
and its analogues in vivo and in tumors is visually displayed, and a new imaging agent is
provided for early tumor diagnosis.
[0034] The following describes the embodiments of the present invention in detail.
The embodiments are implemented on the premise of the technical solutions of the present
invention. Detailed implementations and specific operation processes are given. However,
the protection scope of the present invention is not limited to the following embodiments.
[0035] In the following embodiments, various processes and methods that are not described in detail are conventional methods known in the art. Unless otherwise specified, materials, reagents, devices, instruments, equipment, etc. used in the following examples can be commercially available.
[0036] I-Larotrectinib analogue precursor in step 1
R2 N'N OR3 N 6
[0037] In the above formula, R3 specifically represents H.
[0038] It can be prepared by the following method:
[0039] Step 1: key intermediate 4 and its synthesis
R2 0 R2 0 02 H HN 00 R R1OH NH 2 R
12 3 4
[0040] step 2: key intermediate 8 and its synthesis
C1 N C1 N NO 2 6 NH 2
C SC1 7 N CO 8 HN 6 ; and
[0041] Step 3: Preparation of halogenated larotrectinib analog 9
R R1 N'-N OH -N.-N OH
CI R 16 N N)N HN N N 119 8 HN O 0
[0042] Taking the preparation of (R)-2-F-5-I-Larotrectinib as an example, the
preparation method is as follows:
[0043] step 1: key intermediate 4 and its synthesis
[0044] 1a. Synthesis of (E)-4-(5-fluoro-2-iodophenyl)-4-oxobut-2-enoic acid
1 0 I 0 -z OH
0
F F C 8 H6 FIO: 264.04 C 10H 6 F103: 320.06
[0045] 5-fluoro-2-iodoacetophenone (39.6g, 150mmol) and glyoxylic acid
monohydrate (13.9g, 151mmol) were dosed in a 500mL reactor, and then heated to react
and distilled off water under reduced pressure (95 °C, 0.1Mpa); after 3 hours of reaction,
the reaction mixture was cooled to room temperature, 5% potassium carbonate aqueous
solution (300mL) was then dosed, and the mixture was extracted twice with ethyl acetate,
200mL each time; after the aqueous layer was acidified (10% hydrochloric acid, 300mL),
and extraction was carried out twice with ethyl acetate, 200 mL each time; the organic
phases were combined, rinsed with brine, and dried over anhydrous sodium sulfate, and
the solvent was removed under reduced pressure, thus obtaining an orange solid. The solid
was dissolved in glacial acetic acid (50mL) and concentrated hydrochloric acid (36%,
mL), the mixture was heated to reflux for 4 hours, and the acetic acid was removed under
reduced pressure. The residue was extracted with ethyl acetate (300mL) and rinsed with
brine three times, 1OOmL each time; organic phase was dried over anhydrous sodium
sulfate, and the solvent was removed under reduced pressure, thus obtaining the target product (26.89g, 56%) as a yellow solid with an M.P. of 146 °C.
[0046] 'H NMR (400MHz, DMSO-d6) 6 12.96 (brs, 1H), 8.00-7.74 (m, 3H), 7.30
(t, 1H, J= 8.5 Hz), 6.64 (d, 1H, J= 15.4 Hz).
[0047] MS (El) m/z 320(M+)
[0048] lb. Synthesis of 4-(5-fluoro-2-iodophenyl)-4-oxobutanoic acid
1 0 1 0 OH OH
0 0
F F C 1 0H 6 FI03 : 320.06 C1 0H 8FI03 : 322.07
[0049] 210mL of acetic acid, 75mL of water, and starting material (47.1g,
147mmol) were dosed in a 500mL reaction flask; zinc powder (10.9g, 166mmol) was
dosed in the reaction mixture in batches within about 1 hour in a stirring way; the mixture
was further stirred for 3 hours, reactant was then filtered, the filter cake was rinsed with
ethyl acetate (300mL), the organic phase was rinsed with brine three times, 100mL each
time, and dried over anhydrous sodium sulfate, and the solvent was removed under
reduced pressure, thus obtaining the target product (29.8g, 63%) with an M.P. of 152 °C.
[0050] 'H NMR (400 MHz, CDCl3 ) 12.00 (1H, brs), 7.91-7.71 (3H, m), 3.23 (2H,
t, J= 6.26), 2.57 (2H, t, J = 6.24).
[0051] MS (El) m/z 322 (M+).
[0052] 1c. Synthesis of methyl 4-(5-fluoro-2-iodophenyl)-4,4-dimethoxybutanoate
1 0 | I O0 0 OH 0
0 0
F F C1 0H 8FI03: 322.07 C 13 H 1 6FI04 : 382.17
[0053] The starting material (32.2g, 0.1mol), trimethyl orthoformate (C4H1003=
106.12, 31.84g, 0.3mol) and methanol (90mL) were dosed in a 250mL reaction flask, and
drops of sulfuric acid was then dosed; the mixture was heated to 65 °C to react for 4 hours, TLC tracked the reaction process until the starting material was completely converted, and the solvent was distilled off under reduced pressure. The residue was diluted with isopropyl ether (190 mL), the reaction was quenched with saturated sodium bicarbonate (100 mL), the organic phase was separated, rinsed with brine twice, 120 mL each time, and dried over anhydrous magnesium sulfate, and the solvent was distilled off, thus obtaining the product (32.48g, 85%) which was directly used in the next step.
[0054] 'H NMR (400 MHz, CDC 3 ) 1.29-1.38 (2H, m), 2.25 (2H, t, J = 7.2 Hz),
3.11 (3H, s), 3.17 (6H, s), 7.24-7.28 (1H, m), 7.31-7.38 (2H, m), 7.46 (1H, dt, J = 8.6, 1.4
Hz);
[0055] MS (ESI) m/z 383 [M+H]*.
[0056] 1d. Synthesis of 4-(5-fluoro-2-iodophenyl)-4-oxobutanamide
II I I I I 00 100 O-_ NH 2
0 0
F F C 13H 1 6FI04 : 382.17 C 12 H 1 5FIN03 :367.16
[0057] 100mL of methanol was dosed in a 250mL reaction flask and cooled to
below 0 °C, and ammonia gas was introduced until the solution was saturated (about
-12g); the esterification product (19.lg, 0.05mol) from step I was dosed in 50mL of
methanol to obtain a liquid, the liquid was dropwise dosed in the methanol-ammonia
saturated solution, and the internal temperature was maintained at about 0 °C. After the
liquid was completely dosed dropwise, the reaction solution continued to react for 16
hours at 0 °C. When TLC detected that the esterification product from step I in the
reaction solution basically disappeared, the reaction was stopped, and the solvent was
removed under reduced pressure, thus obtaining an oily product which was used directly
in the next step of reaction.
[0058] MS (ESI) m/z: 368.1(M+H)+.
[0059] le. Synthesis of 5-(5-fluoro-2-iodophenyl)-3,4-dihydro-2H-pyrrole
1 0 I I I N NH 2 (E)
0 F F C 12 H1 5FIN0 3: 367.16 C 10 H 9FIN: 289.09
[0060] Dry tetrahydrofuran (300mL), the amide (18.36g, 0.05mol) from step Id,
and sodium borohydride (29.26g, 0.77mol) were dosed in a 500mL reactor, stirred to be
uniform, and then cooled to 0 °C with an ice bath; in the presence of nitrogen, boron
trifluoride ether solution (36.75mL, 0.3mol) was dosed dropwise within about 2 hours, the
ice bath was removed, the mixture was heated to reflux for 16 hours, TLC detected the
reaction until raw material was completely converted, the reaction solution was cooled to
°C, 6N hydrochloric acid (35mL) was slowly dosed dropwise, the mixture was heated to
reflux for 1 hour, the reaction solution was cooled to 40 °C, and the solvent was removed
under reduced pressure. The residue was diluted with water, neutralized with 10% NaOH
to neutrality, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure, thus obtaining oily
-(5-fluoro-2-iodophenyl)-3,4-dihydro-2H-pyrrole(11.27g,78%).
[0061] The NMR data of the product obtained were as follows:
[0062] 'H NMR, 400 MHz, CD 30D 6: 7.78 (m, 1H), 7.43-7.34 (m, 2H), 3.54 (m,
2H), 2.12 (dt, J = 10.3, 2.0 Hz, 2H), 1.97 (dt, J = 15.8, 7.9 Hz, 2H).
13
[0063] C NMR, 100MHz, CD 30D 6: 176.2, 158.2 (d, J = 260.3), 155.0 (d, J=
10.3), 124.0 (d, J= 3.1), 119.4 (d, J= 23.5), 118.4 (d, J= 23.5), 62.3, 36.5, 21.0.
[0064] If: Synthesis of 2-(5-fluoro-2-iodophenyl)pyrrolidine
F F C 10 H 9FIN: 289.09 C 10H 11 FIN: 291.11
[0065] The oily 5-(5-fluoro-2-iodophenyl)-3,4-dihydro-2H-pyrrole (7.23g,
0.025mol) was dosed in 100mL of a solution of methanol and water (4:1); the mixed
solution was cooled to 0 °C, sodium borohydride (0.95g, 0.025mol) was dosed in batches,
hydrogen was released, and the reaction solution turned into a yellow turbid liquid; 3
hours later, the reaction solution was heated to room temperature, and the solvent was
distilled off. The residue was treated with NaOH and then extracted with isopropyl ether;
the ether layer was dried over anhydrous sodium sulfate overnight and filtered to remove
the solvent, thus obtaining a light yellow oily product (6.23g, 88.3%), which was directly
used into next step of reaction.
[0066] 'H NMR, 400 MHz, CDCl3 6: 7.29 (m, 1H), 7.02 (m, 1H), 6.96 (m, 1H),
4.09 (t, J = 7.8 Hz, 1H), 3.16(m, 1H), 3.04(m, 1H), 2.21-2.30(m, 1H), 1.77-1.95(m, 3H),
1.57-1.67(m, 1H).
[0067] LC-ESI-MS (m/z) 292 [M+H]*.
[0068] Step 2: Synthesis of key intermediate 8
[0069] 2a. Synthesis of 5-chloropyrazolo[1,5-a]pyrimidin-3-amine
CI N CI N NO 2 NH 2
C6 H 3 CIN 40 2 :198.57 C 6 H 5CIN 4 :168.58
[0070] 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine compound (25g, 0.125mol),
ethanol (250mL), and iron powder (75g, 1.25mol) were dosed in a 1000mL reaction flask
and heated to reflux in the presence of nitrogen, and ammonium chloride (66.5g, 1.25mol)
aqueous solution (250mL) was dosed dropwise at the same time within about 1 hour; the
reflux reaction was continued for 6 hours; TLC tracked the reaction until the reaction was
completed, the reactant was concentrated to paste under reduced pressure. The residue was
diluted with water (100mL), then layered with dichloromethane and extracted 4-6 times,
200mL each time; the organic phases were combined, rinsed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced pressure, thus
obtaining 5-chloropyrazolo[1,5-a]pyrimidin-3-amine compound (419.7g, 93.5%).
[0071] 'H NMR, 400 MHz, CD30D 6:9.29(d,J= 7.2Hz,1H),8.71(s,1H),8.16(d,J
7.2Hz,1H), 5.92(s,2H):
[0072] MS(ESI)m/z: 169.8[M+H]+.
[0073] 2b. Synthesis of 5-chloro-3-isocyanatopyrazolo[1,5-a]pyrimidine
CI N CI N NH 2 N-CZO C6H5CIN4: 168.58 C 7H 3CIN 4 0:194.58
[0074] Triphosgene (9.91g, 33.38mmol) was dissolved in 50ml of tetrahydrofuran,
-chloropyrazolo [1,5-a]pyrimidin-3-amine (16.86g, 0.1mol) and triethylamine (0.47g,
4.64mmol) were dosed, and the reaction system was stirred to react for 1 hour at 25°C. A
suspension of 5-chloro-3-isocyanatopyrazolo[1,5-a]pyrimidine was obtained, and the
product was directly subjected to the next reaction without purification.
[0075] 2c. Synthesis of
(S)-N-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
NLCZ::O O C7 H 3 CIN 4 0:194.58 C 11 H 12CIN 5 02 : 281.70
[0076] Sodium bicarbonate solution (80ml, 0.5M, 40mmol) was dosed in a 250mL
reactor, (S)-pyrrol-3-ol (79g, 55mmol) was then dosed, the isocyanate solution prepared in
step 9b (62mL, 100mmol, calculated on the basis of 5 -chloropyrazolo
[1,5-a]pyrimidin-3-amine) was dosed dropwise, and the temperature was maintained at
about 0 °C; and then the mixture was further stirred at 0 °C for 3 hours and then heated to
°C to further react for 5 hours; the reaction solution was cooled to room temperature,
extracted three times with ethyl acetate, 100 mL each time. The organic phases were
combined, rinsed with 2N hydrochloric acid, then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and elution with ethyl acetate/petroleum ether (5:5, v/v) was carried out, thus obtaining a product (22g, 78%).
[0077] 'H NMR(300MHz,d 6 DMSO)6 : 9.26(d,J = 7.2Hz 1H), 8.73(s,1H),
8.78(s,1H), 8.07(d,J= 7.2Hz,1H),4.02(m,1H), 3.62(m,2H),3.48(m,2H),2.36(m,2H);
[0078] MS(ESI)m/z: 282[M+H]+.
[0079] Step 3: Preparation of halogenated larotrectinib analog 9
[0080] Synthesis of halogenated larotrectinib compound (R)-5-F-2-I-Larotrectinib
NN I) N N HN-fN -~ HN K N6
C 11H 12CIN 502 :281.70 C 10H 11FIN:291.11 C 21H 22 FIN 602: 536.35 2-(5-fluoro-2-iodophenyl)pyrrolidine (R)-5-F-2-1-Larotrectinib
[0081] Pyrazolo (1,5a) pyrimidine compound (30g, 106mmol), 5-F-2-I-pyrrole
compound (30.9g, 106mmol) and 1,4-dioxane (150mL) were dosed in a reaction flask,
N,N-lutidine (C7H10N2=122.17, 25.9g, 212mmol) was dosed dropwise, and the reaction
temperature was maintained within 30 °C; then, the reaction was continued for 6 hours and
the whole reaction was under the control of TLC; the post treatment was carried out in the
same way as that in Example 6, and the racemic mixture 5-F-2-I-Larotrectinib (53.8g,
94.6%) was obtained as a white solid. Then, by chiral LC separation and purification,
(R)-5-F-2-I-Larotrectinib was obtained as a pure white chiral solid, and
(S)-5-F-2-I-Larotrectinib was obtained as a pure white chiral solid.
[0082] 1H NMR(300MHz,d 6 DMSO) 6 = 9.12(d,J = 7.2Hz 1H), 8.73(s,1H),
8.78(s,1H),
8.07(d,J=7.2Hz,1H),6.8-7.3(m,3H),4.17(m,1H),4.02(m,1H),3.62(m,2H),3.48(m,2H),1.75
2.86(m,8H);
[0083] MS(ESI)m/z: 536.3(M+H)+.
[0084] The preparation process of the compound of the invention will be described
in detail below by examples, where
[0085] Examples 1 to 42 describe hydroxyl protection in the first step to prepare I
hydroxyl protected Larotrectinib compound
[0086] Example 1
[0087] Preparation of I-Bz-2-Larotrectinib or I-Bz-5-Larotrectinib by benzoyl
chloride esterification
[0088] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
pyridine (240mmol, 18.98g) and benzoyl chloride (80mmol, 11.4g) were dosed in the
solution at the same time; the mixture was stirred at room temperature to react for 3 hours
under the control of TLC; at the end of the reaction, the mixture was poured into water and
the organic layer was separated; the organic layer was sequentially washed with dilute HCl
to remove pyridine and acidify unreacted acid chloride), with dilute NaOH (preferably
saturated sodium bicarbonate, 1OOmL) to wash off acid, and then with saturated sodium
chloride to neutral, and most of the water in the organic layer was removed. The organic
layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to
remove the solvent, and the residue was crystallized with ethanol-methyl tert-butyl ether
(4:1, 180mL), thus obtaining the product I-Bz-2-Larotrectinib as a white solid with a yield
of 88% (70.4mmol, 45.1g). The synthesis route was as follows: F F
Nf 2 0
C 21H 22FIN 60 2: 536.35 C2gH 2 6FIN 603:640.46 I-2- Larotrectinib I - Bz-2-Larotrectinib
[0089] Example 2
[0090] Preparation of I-Bz-5-Larotrectinib by benzoyl chloride esterification
[0091] The preparation method was the same as that in Example 1. The compound
1-5-Larotrectinib was used as the raw material to obtain the product I-Bz-5-Larotrectinib
as a white solid with a yield of 88% (70.4mmol, 45.1g). The route was as follows:
N OH 0 FI F NNN NNK F N0
C 21H 22F1N 602: 536.35 C 2eH 26FIN60 3:640.46 I-5- Larotrectinib I - Bz-5-Larotrectinib
[0092] Example 3
[0093] Preparation of I-Piv-2-Larotrectinib by pivaloyl chloride esterification
[0094] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
saturated sodium bicarbonate solution (23g) and pivaloyl chloride (80mmol, 9.64g) were
dosed in the solution at the same time; the mixture was stirred at room temperature to
react for 24 hours under the control of TLC; at the end of the reaction, the mixture was
poured into water and the organic layer was separated; the organic layer was sequentially
washed with IN sodium hydroxide (OOmL) and saturated brine (OOmL), dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the
solvent; the residue was crystallized with methanol-isopropyl ether (7:3, 150 mL), thus
obtaining the product I-Piv-2-Larotrectinib as a white solid with a yield of 85% (68mmol,
42.2g). The route was as follows:
N...N 0 N-,N OH 00 N NN HNN
C21 H 22 FIN 60 2 : 536.35 C26H 30FING0 3:620.47 I - 2-Larotrectinib I - Piv-2-Larotrectinib
[0095] Example 4
[0096] Preparation of I-Piv-5-Larotrectinib by pivaloyl chloride esterification
[0097] The preparation method was the same as that in Example 3. The compound
1-5-Larotrectinib was used as the raw material to obtain the product I-Piv-5-Larotrectinib
as a white solid with a yield of 85% (70.4mmol, 42.2g). The route was as follows:
II 0
0 N-N OH F NN F NN
C21H 22FIN 60 2: 536.35 C 26H 30FINS0 3:620.47 I - 5-Larotrectinib I - Piv-5-Larotrectinib
[0098] Example 5
[0099] Preparation of I-Ac-2-Larotrectinib by acetyl chloride esterification
[00100] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
triethylamine (240mmol, 24.2g) and acetyl chloride (80mmol, 6.28g) were dosed in the
solution at the same time; the mixture was stirred at room temperature to react for 3 hours
under the control of TLC; at the end of the reaction, the mixture was poured into water and
the organic layer was separated; the organic layer was sequentially washed with saturated
ammonium chloride solution (100mL), saturated sodium bicarbonate, and water, dried
over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove
the solvent; the residue was crystallized with acetone-petroleum ether (5:2, 110 mL), thus obtaining the product I-Ac-2-Larotrectinib as a white solid with a yield of 96.9%
(77.52mmol, 44.83g).
NN N N6
C21 H22 FIN 60 2 : 536.35 C23 H24 FIN 603:578.39 I - 2-Larotrectinib I - Ac-2-Larotrectinib
[00101] Example 6
[00102] Preparation of I-Ac-5-Larotrectinib by acetyl chloride esterification
[00103] The preparation method was the same as that in Example 5. The compound
1-5-Larotrectinib was used as the raw material to obtain the product I-Ac-5-Larotrectinib
as a white solid with a yield of 96.5% (77.2mmol, 44.7g). The route was as follows:
OH 0N..-N 0O1 Z NN F N N F
1 0
C21 H22 FIN 6 02 : 536.35 C23H 24FIN 0 3:578.39 I - 5-Larotrectinib I - Ac-5-Larotrectinib
[00104] Example 7
[00105] Preparation of I-Tf-2-Larotrectinib by trifluoroacetic anhydride
esterification
[00106] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
2,4,6-trimethylpyridine (240mmol, 29.1g) as a base and trifluoroacetic anhydride
(80mmol, 16.8g) were dosed in the solution at the same time; the mixture was stirred at
room temperature to react for 8 hours under the control of TLC; at the end of the reaction,
the mixture was poured into water and the organic layer was separated; the organic layer
was sequentially washed with 5% dilute hydrochloric acid solution (100mL) and saturated
brine (100mL), dried over anhydrous magnesium sulfate, and concentrated under reduced
pressure to remove the solvent; the residue was crystallized with isopropyl
acetate-petroleum ether (6:1, 120mL), thus obtaining the product I-Tf-2-Larotrectinib as a
white solid with a yield of 94% (75.2mmol, 59.44g). The route was as follows:
OH O :P N-N OH CF3
0~ 2 0
C21 H22 FIN 6 02 : 536.35 C 23H 2 1F 4 1N 6 03:632.36 I - 2-Larotrectinib I - Tf-2-Larotrectinib
[00107] Example 8
[00108] Preparation of I-Tf-5-Larotrectinib by trifluoroacetic anhydride
esterification
[00109] The preparation method was the same as that in Example 7. The compound
1-5-Larotrectinib was used as the raw material to obtain the product I-Tf-5-Larotrectinib as
a white solid with a yield of 94% (75.2mmol, 59.4g). The route was as follows:
'®N,"N OH N'N O CF F N ' F CF3
1 2 0
C21 H22 FIN 6 0 2 : 536.35 C 23 H 21 F 4 1N 6 03:632.36 I -5-Larotrectinib I - Tf-5-Larotrectinib
[00110] Example 9
[00111] Preparation of I-DCAc-2-Larotrectinib by dichloroacetyl chloride
esterification
[00112] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
pyridine (240mmol, 19.0g) and dichloroacetyl chloride (80mmol, 11.79g) were dosed in
the solution at the same time; the mixture was stirred at room temperature to react for 2
hours under the control of TLC; at the end of the reaction, the mixture was poured into
water and the organic layer was separated; the organic layer was sequentially washed with
saturated ammonium chloride solution (1OOmL), saturated sodium bicarbonate, and water,
dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to
remove the solvent; the residue was crystallized with acetone-petroleum ether (5:2, 110
mL), thus obtaining the product I-DCAc-2-Larotrectinib as a white solid with a yield of
91.6% (73.28mmol 47.43g). The route was as follows:
00I N'N OH N..N OOCCHC12
N N N N- CT ~HN-fN O 0 C2 1H 2 2FIN60 2 : 536.35 C2 3H2 2Cl 2FIN6 0 3 :647.27 1-2- Larotrectinib I-DCAc -2- Larotrectinib
[00113] Example 10
[00114] Preparation of I-DCAc-5-Larotrectinib by dichloroacetyl chloride
esterification
[00115] The preparation method was the same as that in Example 9. The compound
1-5-Larotrectinib was used as the raw material to obtain the product
I-DCAc-5-Larotrectinib as a white solid with a yield of 91% (73mmol, 47g). The route
was as follows:
FN.-N OH N' OOCCHC1 2
O 0 C 21H 22 FIN 6 02 : 536.35 C 23 H22 Cl2FIN 6 0 3 :647.27 1-5- Larotrectinib I-DCAc -5- Larotrectinib
[00116] Example 11
[00117] Preparation of I-Moc-2-Larotrectinib by methyl chloroformate
esterification
[00118] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
pyridine (240mmol, 19.0g) and methyl chloroformate (80mmol, 47.2g) were dosed in the
solution at the same time; the mixture was stirred at room temperature to react for 8 hours
under the control of TLC; at the end of the reaction, the mixture was poured into water and
the organic layer was separated; the organic layer was washed twice with water,1OOmL
each time, dried over anhydrous magnesium sulfate, and concentrated under reduced
pressure to remove the solvent; the residue was crystallized with ethyl acetate-petroleum
ether (6:1, 140mL), thus obtaining the product I-Moc-2-Larotrectinib as a white solid with
a yield of 96.5% (77.2mmol, 45.88g). F F
NN N N N 1 -f2 o
C 21H 22FIN60 2: 536.35 25 C 23H 24FIN 60 3:594.39 I--2-Larotrectinib I - Moc-2-Larotrectinib
[00119] Example 12
[00120] Preparation of I-Moc-5-Larotrectinib by methyl chloroformate
esterification
[00121] The preparation method was the same as that in Example 11. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-Moc-5-Larotrectinib as a white solid with a yield of 91% (73mmol, 47g). The route was
as follows:
1 -2
C 21H 22FIN 60 2: 536.35 C23 H24FIN6O 3:594.39 I--5-Larotrectinib I - Moc-5-Larotrectinib
[00122] Example 13
[00123] Preparation of I-Eoc-2-Larotrectinib by ethyl chloroformate esterification
[00124] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
N,N-Diisopropylethylamine (240mmol, 30.48g) and ethyl chloroformate (80mmol, 8.68g)
were dosed in the solution at the same time; the mixture was stirred at room temperature
to react for 6 hours under the control of TLC; at the end of the reaction, the mixture was
poured into water and the organic layer was separated; the organic layer was sequentially
washed with 5% dilute hydrochloric acid solution (100mL) and saturated brine (100mL),
dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to
remove the solvent; the residue was crystallized with isopropyl acetate-petroleum ether
(6:1, 120mL), thus obtaining the product I-Eoc-2-Larotrectinib as a white solid with a
yield of 94.3% (75.2mmol, 59.44g). The route was as follows:
F F 0
N.~.N O O .,' N N'I OH 0 NN N1 N ON~2 N6
12 o
C 21H22FIN 602 : 536.35 C24H 26 FIN6O 4 :608.41 I - 2-Larotrectinib I -2- Eoc-Larotrectinib
[00125] Example 14
[00126] Preparation of I-Eoc-5-Larotrectinib by ethyl chloroformate esterification
[00127] The preparation method was the same as that in Example 13. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-Eoc-5-Larotrectinib as a white solid with a yield of 94% (75mmol - 75g). The route was
as follows:
OH 0 F N H F N N O
2 0 N 1 Nf
C21 H 22 FIN 6 0 2 : 536.35 C24 H2 6FIN 6 04:608.41 I - 5-Larotrectinib I - Eoc-5-Larotrectinib
[00128] Example 15
[00129] Preparation of I-Boc-2-Larotrectinib by Boc anhydride esterification
[00130] 400 mL of chloroform and compound1-2-Larotrectinib (80mmol, 42.9g)
were dosed in a 2000 ml reaction flask and stirred at room temperature to be dissolved;
DMAP (4mmol, 0.5g), KOH (240mmol, 13.44g), and Boc anhydride (80mmol, 17.46g)
were dosed in the solution at the same time; the mixture was stirred at room temperature
to react for 16 hours under the control of TLC; at the end of the reaction, the mixture was
poured into water and the organic layer was separated; the organic layer was sequentially
washed with 5% dilute hydrochloric acid solution (100mL) and saturated brine (100mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent; the residue was crystallized with isopropyl acetate-petroleum ether
(6:1, 120mL), thus obtaining the product I-Boc-2-Larotrectinib as a white solid with a
yield of 94% (75.2mmol, 47.86g). The route was as follows:
N.N OH N'N OBoc
NN N N3
C 21 H 22 FIN 6 02 : 536.35 C 2GH 30FIN 604: 636.47
1 - 2-Larotrectinib I - Boc-2-Larotrectinib
[00131] Example 16
[00132] Preparation of I-Boc-5-Larotrectinib by Boc anhydride esterification
[00133] The preparation method was the same as that in Example 15. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-Boc-5-Larotrectinib as a white solid with a yield of 94% (75mmol, 47g).
[00134] Example 17
[00135] Preparation of I-Troc-2-Larotrectinib by 2,2,2-trichloroethyl chloroformate
(Troc) esterification as the following route:
OH SN N CC 3
N 0 N~ CI ci~ OCII 00 C 21H22FIN 60 2: 536.35 C 24H 23Ci 3FING04:711.74 I - 2-Larotrectinib I -Troc-2-Larotrectinib
[00136] 150 mL of DCM, compound 1-2-Larotrectinib (80mmol, 42.91g) and
pyridine=79 (2.5e, 200mmol, 15.80g) were dosed in a 500 ml reaction flask and stirred at
room temperature for 5 minutes; 2,2,2-trichloroethyl chloroformate (C3H2C1402=211.85,
1.2e, 96mmol, 13.66g, 20.34mmol) was dropwise dosed and dissolved in the DCM
(30ml) solution, and the solution was stirred at room temperature for 3 hours under the
control of TLC; at the end of the reaction, the mixture was poured into water and the
organic layer was separated; the organic layer was sequentially washed with 3% HCl and
saturated sodium bicarbonate and then washed three times with brine (80gx3); the organic
phase was dried over anhydrous sodium sulfate and filtered with suction, the filtrate was
concentrated to be viscous, and the residue was subjected to silica gel column
chromatography (petroleum ether: ethyl acetate = 5:1), thus obtaining the product
I-Troc-2-Larotrectinib as a white solid (91.2%, 51.93g).
[00137] Example 18
[00138] Preparation of I-Troc-5-Larotrectinib by 2,2,2-trichloroethyl chloroformate
(Troc) esterification
[00139] The preparation method was the same as that in Example 17. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-Boc-5-Larotrectinib as a white solid with a yield of 91% (72.8mmol 51g).
[00140] Example 19
[00141] Preparation of I-Teoc-2-Larotrectinib by trimethylsilyl ethoxycarbonyl
chloride (Teoc) esterification
F F 0
-N OH -N O0
SN N6 N S 0 0 C21 H 22FIN 60 2 :536.35 C 27 H 34 FIN 60 4 Si:680.59 I -2-Larotrectinib I -Teoc-2-Larotrectinib
[00142] 150 mL of dichloromethane, compound1-2-Larotrectinib (80mmol, 42.91g)
and pyridine=79 (2.5e, 200mmol, 15.80g) were dosed in a 500 ml reaction flask and cooled to 0-5 °C; trimethylsilyl ethoxycarbonyl chloride (Teoc) (C 6H3 ClO 2 Si= 180.70,
2.Oeq,28.91g, 160mmol) was dropwise dosed slowly and dissolved in the DCM (30ml)
solution; then, the obtained solution was further stirred at room temperature for 3 hours
under the control of TLC; at the end of the reaction, 5 mL of methanol was dosed and the
mixture was stirred to react for half an hour at room temperature; the mixture was poured
into water and the organic layer was separated; the organic layer was sequentially washed
with 3% HCl and saturated sodium bicarbonate and then washed three times with brine
(80gx3); the organic phase was dried over anhydrous sodium sulfate and filtered with
suction, the filtrate was concentrated to be viscous, and the residue was subjected to silica
gel column chromatography (petroleum ether: ethyl acetate = 5:1), thus obtaining the
product I-Teoc-2-Larotrectinib as a white solid (83.6%, 45.52g).
[00143] Example 20
[00144] Preparation of I-Teoc-5-Larotrectinib by trimethylsilyl ethoxycarbonyl
chloride (Teoc) esterification
[00145] The preparation method was the same as that in Example 19. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-Teoc-5-Larotrectinib as a white solid with a yield of 83% (66.4mmol, 45g).
[00146] Example 21
[00147] Preparation of I-TBS-2-Larotrectinib by tert-butyldimethylchlorosilane
etherification
C27H36FING0 2Si:650.61 C21 H 22 FIN 6 0 2 : 536.35 I - 2-Larotrectinib I -TBS-2-Larotrectinib
[00148] 150 mL of DMF was dosed in a 500 ml reaction flask and cooled to 0 °C,
and then compound 1-2-Larotrectinib (80mmol, 42.91g), tert-butyldimethylchlorosilane
(TBS-Cl, C6H15ClSi= 150.72) (1.3eq, 104mml, 15.67g), and imidazole (C 3 H 4N 2 = 68.08,
1.5eq, 120mmol, 8.17g) were sequentially dosed; the mixture was stirred at room
temperature and reacted overnight usually until the conversion was complete under the
control of TLC; the mixture was diluted with an equal volume of chloroform, washed
three times with water and then washed once with brine. The organic layer was dried,
concentrated under reduced pressure, and the residue was subjected to silica gel column
chromatography (petroleum ether: ethyl acetate=5:1), thus obtaining the product
I-TBS-2-Larotrectinib (86.8%, 45.17g).
[00149] Example 22
[00150] Preparation of I-TBS-5-Larotrectinib by tert-butyldimethylchlorosilane
etherification
[00151] The preparation method was the same as that in Example 21. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-TBS-5-Larotrectinib as a white solid with a yield of 86% (68.8mmol, 45g).
[00152] Example 23
[00153] Preparation of I-TIPS-2-Larotrectinib by triisopropylchlorosilyl
etherification
NN-i N N N,
C 21H 22FIN 602 : 536.35 CaoH 42 FIN 602Si:692.69 I - 2-Larotrectinib I - TIPS-2-Larotrectinib
[00154] 150 mL of DMF was dosed in a 500 ml reaction flask and cooled to 0 °C,
and then compound 1-2-Larotrectinib (80mmol, 42.91g), triisopropylchlorosilane (TIPSCl,
C9H21ClSi = 192.8, 1.3eq, 104mmol, 20.05g), and imidazole (C3H4N2 = 68.08, 1.3eq,
104mmol, 7.07g) were sequentially dosed; the mixture was stirred at room temperature
and reacted overnight usually until the conversion was complete under the control of TLC;
the mixture was diluted with an equal volume of chloroform, washed three times with
water and then washed once with brine. The organic layer was dried, concentrated under
reduced pressure, and the residue was subjected to silica gel column chromatography
(petroleum ether: ethyl acetate=5:1), thus obtaining the product I-TIPS-2-Larotrectinib
(88.8%, 49.21g).
[00155] Example 24
[00156] Preparation of I-TIPS-5-Larotrectinib by triisopropylchlorosilyl
etherification
[00157] The preparation method was the same as that in Example 23. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-TIPS-5-Larotrectinib as a white solid with a yield of 88% (70.4 mmol, 49g).
[00158] Example 25
[00159] Preparation of I-TBDPS-2-Larotrectinib by tert-Butyldiphenylchlorosilane
etherification F F
0 0 C 21H 22FIN 602 : 536.35 C 37H 40FINS0 2Si:774.75 I - 2-Larotrectinib I - TBDPS-2-Larotrectinib
[00160] 100 mL of THF, compound 1-2-Larotrectinib (80mmol, 42.91g), and
imidazole (2eq, 160mmol, 10.89g) were sequentially dosed in a 500 ml reaction flask and
stirred to react for half an hour, and tert-butyldiphenylchlorosilane (TBDPSCl, 1.5eq,
120mmol, 32.98g) was then dosed in the solution; the mixture was stirred at 25 °C and
completely reacted under the control of TLC; the mixture was diluted with 300mL of
chloroform, and washed once with ammonium chloride solution (1OOmL, containing 37.2g of ammonium chloride), washed with saturated sodium bicarbonate twice, 100ml each time, and further washed once with brine (100ml), the organic phase was dried over anhydrous magnesium sulfate, and filtered; the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=5:1), thus obtaining the product I-TBDPS-2-Larotrectinib (85.7%,
53.12g).
[00161] Example 26
[00162] Preparation of I-TBDPS-5-Larotrectinib by tert-Butyldiphenylchlorosilane
etherification
[00163] The preparation method was the same as that in Example 25. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-TBDPS-5-Larotrectinib as a white solid with a yield of 86% (68.8mmol 53g).
[00164] Example 27
[00165] Preparation of I-PMB-2-Larotrectinib by PMB-(p-Methoxybenzyl)ether
F F OMe
P'NN OH ..-- N O N NN N N3 N
10
C 21H 22FIN 602 : 536.35 C2 9H 30FING0 3:656.50 I - 2-Larotrectinib I - PMB-2-Larotrectinib
[00166] 100 mL of DMF and the dissolved solution of compound -2-Larotrectinib
(80mmol, 42.91g) were dosed in a 500 ml reaction flask; in the presence of nitrogen,
sodium hydrogen (1.3e, 104mmol, 2.5g) cooled to 0 °C was dissolved in the DMF (20mL)
solution; the mixture was stirred at 0 °C for 30 minutes; p-methoxybenzyl bromide (1.3eq,
104mmol, 201.0g) was dosed dropwise in the above solution, and then a catalytic amount
of crown ether was dosed; the reaction solution was further stirred at room temperature for
16 hours under the control of TLC till the end of the reaction; methanol was slowly dosed to quench the reaction; the solution was diluted with chloroform and water and then washed three times with water and twice with brine; the organic layer was dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=5:1), thus obtaining the product I-PMB-2-Larotrectinib (82.8%, 44.15g).
[00167] Example 28
[00168] Preparation of I-PMB-5-Larotrectinib by P-methoxybenzyl etherification
(PMB-(p-Methoxybenzyl)ether)
[00169] The preparation method was the same as that in Example 27. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-PMB-5-Larotrectinib as a white solid with a yield of 83% (66.4mmol, 43.6g).
[00170] Example 29
[00171] Preparation of I-MOM-2-Larotrectinib by chloromethyl methyl ether
etherification
N N QNK N N6
1 i 2 0
C 21H 22FIN 6 02: 536.35 C 23H 26FIN 60 3:580.40 I - 2-Larotrectinib I - MOM-2-Larotrectinib
[00172] 180mL of anhydrous DCM, compound1-2-Larotrectinib (80mmol, 42.91g),
and anhydrous N,N-diisopropylethylamine (2.0 eq, 160mmol, 20.68g) were dosed in a 500
mL reaction flask in the presence of nitrogen, and the reaction mixture was cooled to 0 °C;
chloromethyl methyl ether (MOM-Cl, 1.5eq, 120mmol, 9.66g) was dosed; the mixture
was heated to room temperature and stirred to react completely for about 8 hours or more
under the control of TLC; the reaction solution was washed once with ammonium chloride solution (100mL, containing 37.2g of ammonium chloride), washed twice with saturated sodium bicarbonate, 100ml each time, and washed once with brine (100ml); the organic phase was dried over anhydrous magnesium sulfate and filtered; the mixture was concentrated under reduced pressure; and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=5:1), thus obtaining the product
I-MOM-2-Larotrectinib (74.4%, 34.54g).
[00173] Example 30
[00174] Preparation of I-MOM-5-Larotrectinib by chloromethyl methyl ether
etherification
[00175] The preparation method was the same as that in Example 29. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-MOM-5-Larotrectinib as a white solid with a yield of 74% (59mmol, 34g).
[00176] Example 31
[00177] Preparation of I-MEM-2-Larotrectinib by methoxyethoxymethyl chloride
etherification
1 2 0
C 21H22FIN 602 : 536.35 C 2sH 30FIN 604 :624.46 1 -2- Larotrectinib I - MEM-2-Larotrectinib
[00178] 180mL of dry DCM, compound 1-2-Larotrectinib (0.8mmol), and
methoxyethoxymethyl chloride (MEM-Cl, 1.5eq, 120mmol, 14.95g) were dosed in a 500
mL reaction flask, and N, N-Diisopropylethylamine (1.5eq, 120mmol, 15.51g) was then
dosed; the reaction mixture was stirred at room temperature and completely reacted for
about 5 hours under the control of TLC; the reaction mixture was diluted with DCM
(180mL), and the obtained mixture was then washed twice with water, 100ml each time and then washed with brine (100ml); the organic phase was dried over anhydrous magnesium sulfate, and filtered; the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=5:1), thus obtaining the product I-MEM-2-Larotrectinib (76.8%, 38.37g).
[00179] Example 32
[00180] Preparation of I-MEM-2-Larotrectinib by methoxyethoxymethyl chloride
etherification
[00181] The preparation method was the same as that in Example 30. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-MEM-5-Larotrectinib as a white solid with a yield of 76% (60.8mmol - 38g).
[00182] Example 33
[00183] Preparation of I-SEM-2-Larotrectinib by 2-(trimethylsilyl)ethoxymethyl
chlorideetherification
N N QKSi N N
C 21 H 22 FIN 6 02 :536.35 C27 H 36FIN 6 0 3 Si:666.61 I - 2-Larotrectinib I -SEM-2-Larotrectinib
[00184] 180mL of anhydrous DCM, compound1-2-Larotrectinib (80mmol, 42.91g),
and N,N-diisopropylethylamine (320mmol, 41.36g) were dosed in a 500 mL reaction flask;
2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 240mmol, 40.01g) was dosed in the
reaction mixture mixture at 25 °C; the obtained mixture was stirred at 25 °C to react
completely under the control of TLC; the reaction solution was washed once with
ammonium chloride solution (100mL, containing 37.2g of ammonium chloride), washed
twice with saturated sodium bicarbonate, 100ml each time, and washed once with brine
(100ml); the organic phase was dried over anhydrous magnesium sulfate and filtered; the
mixture was concentrated under reduced pressure; and the residue was subjected to silica
gel column chromatography (petroleum ether: ethyl acetate=5:1), thus obtaining the
product I-SEM-2-Larotrectinib (86.8%, 46.28g).
[00185] Example 34
[00186] Preparation of I-SEM-5-Larotrectinib by 2-(trimethylsilyl)ethoxymethyl
chloride etherification
[00187] The preparation method was the same as that in Example 33. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-SEM-5-Larotrectinib as a white solid with a yield of 86% (68.8mmol, 46g).
[00188] Example 35
[00189] Preparation of I-THP-2-Larotrectinib by tetrahydropyran etherification
N OH 0 '
00
C 21H22FIN 60 2: 536.35 C 26H 30FIN 603 :620.47 I - 2-Larotrectinib I -THP-2-Larotrectinib
[00190] 150 mL of DCM, compound 1-2-Larotrectinib (80mmol, 42.91g) and
pyridine p-toluenesulfonate (0.40g, 1.56mmol) were dosed in a 500 ml reaction flask and
stirred for 5 minutes; 3, 4-Dihydro-2H-pyran (13.66g, 168.46mmol) was dropwise dosed
and dissolved in the DCM (50ml) solution, and the solution was stirred overnight at room
temperature and then washed three times with brine (80gx3); the organic phase was dried
over anhydrous sodium sulfate and filtered with suction, the filtrate was concentrated to be
viscous, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1), thus obtaining the product I-THP-2-Larotrectinib (98.6%,
48.94g).
[00191] Example 36
[00192] Preparation of I-THP-5-Larotrectinib by tetrahydropyran etherification
[00193] The preparation method was the same as that in Example 35. The
compound I-5-Larotrectinib was used as the raw material to obtain the product
I-THP-5-Larotrectinib as a white solid with a yield of 98% (78.4mmol - 48g).
[00194] Example 37
[00195] Preparation of I-EE-2-Larotrectinib by 1-ethoxyethanol acetate (EE)
etherification
NN oN N 0O O
C 2 1H 2 2 FIN 602 :536.35 C 25H30FIN 6 03:608.46 I - 2-Larotrectinib I -EE-2-Larotrectinib
[00196] 150 mL of DCM, compound 1-2-Larotrectinib (80mmol, 42.91g), pyridine
p-toluenesulfonate (0.40g, 1.56mmol) and 1-ethoxyethanol acetate (C6H1203=132.16,
1.5e, 120mmol, 15.86g) were dosed in a 500 ml reaction flask and stirred for 1.5 hours at
room temperature; the solution was washed three times with brine (80gx3); the organic
phase was dried over anhydrous sodium sulfate and filtered with suction, the filtrate was
concentrated, and the residue was subjected to silica gel column chromatography
(petroleum ether: ethyl acetate = 5:1), thus obtaining the product I-EE-2-Larotrectinib
(85.7%, 41.72g).
[00197] Example 38
[00198] Preparation of I-EE-5-Larotrectinib by 1-ethoxyethanol acetate (EE) etherification
[00199] The preparation method was the same as that in Example 37. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-EE-5-Larotrectinib as a white solid with a yield of 85% (68mmol 41g).
[00200] Example 39
[00201] Preparation of I-Als-2-Larotrectinib by allyl sulfonyl chloride etherification
F F 0
C 21H 22 FIN 6 02 : 536.35 C 24H2 6FIN 604S:640.47 I - 2-Larotrectinib I - Als-2-Larotrectinib
[00202] 180mL of DCM and compound 1-2-Larotrectinib (80mmol, 42.91g) were
dosed in a 500 ml reaction flask and then cooled to -30 °C, and allylsulfonyl chloride Als
(C3H5ClO2S=140.58, 2.5eq, 200mmol, 28.12g) was then dosed to react at this
temperature for 2 hours; the reaction mixture was heated to room temperature and stirred
to completely react for about 6 hours under the control of TLC; the reaction mixture was
concentrated under reduced pressure, the residue was dissolved in ethyl acetate (120 mL),
the mixture was washed twice with saturated sodium bicarbonate solution, 80mL each
time and then washed once with brine (80 mL); the organic phase was dried over
anhydrous magnesium sulfate, and filtered; the mixture was concentrated under reduced
pressure, and the residue was subjected to silica gel column chromatography (petroleum
ether: ethyl acetate=5:1), thus obtaining the product I-Als-2-Larotrectinib (86%, 44.06g).
[00203] Example 40
[00204] Preparation of I-Als-5-Larotrectinib by allyl sulfonyl chloride etherification
[00205] The preparation method was the same as that in Example 39. The compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-Als-5-Larotrectinib as a white solid with a yield of 86% (68.8mmol 44g).
[00206] Example 41
[00207] Preparation of I-PMP-2-Larotrectinib by P-methoxyphenol etherification
(PMP-(p-Methoxyphenyl)ether)
F F OMe
10
C 2 1 H 22 FIN 602 : 536.35 C2sH 2aFINGO 3:642.47 I - 2-Larotrectinib I - PMP-2-Larotrectinib
[00208] 100mL of THF, compound 1-2-Larotrectinib (80mmol, 42.91g),
triphenylphosphonium (1.3eq, 104mmol, 31.65g), diethyl azodicarboxylate (1.3eq,
104mmol, 18.11g), and p-methoxyphenol (3eq, 240mmol, 29.79g) were dosed in a 500 ml
reaction flask; the reaction mixture was heated to 80 °C, and stirred to completely react for
about 2 hours under the control of TLC; the mixture was concentrated under reduced
pressure, and the residue was subjected to silica gel column chromatography (petroleum
ether: ethyl acetate=5:1), thus obtaining the product I-PMP-2-Larotrectinib (81.3%,
41.6g).
[00209] Example 42
[00210] Preparation of I-PMP-5-Larotrectinib by P-methoxyphenol etherification
(PMP-(p-Methoxyphenyl)ether)
[00211] The preparation method was the same as that in Example 41. The
compound 1-5-Larotrectinib was used as the raw material to obtain the product
I-PMP-5-Larotrectinib as a white solid with a yield of 81% (64.8mmol, 43.6g).
[00212] Step 2: Preparation of labeled precursor
[00213] Example 43
[00214] Preparation of labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib
' 1-N OOCC6 H, FCO- N'-N OOCCH,
N N F3CCOO N N
0 0 C 2gH 26FINS0 3:640.46 C3 2H 2BF 7 NSOy:868.50
I - Bz-2-Larotrectinib I -TfAc- Bz-2-Larotrectinib
0 -N OOCC 6 H5 F N N OOCC 6 H5 1
F 3 CCOO c~i N HN-.-IY N6 H O N HN N
O ""H 0
C32H 28F 71NS0 7:868.50 H C41 H42FIN 60 7:876.72 I-TfAc- Bz-2-Larotrectinib I(Ill)-SPIAd - Bz-2-Larotrectinib
[00215] 0.39mL of trifluoroacetic acid and 0.13mL of chloroform were dosed in a
1OmL reaction flask; urea-hydrogen peroxide complex (CO(NH2)2-H202 = 94.07,
1.36g,14.5mmol) and I-Bz-2-Larotrectinib (70.45mg, 0.11mmol) were then ndosed in the
mixed solution in a stirring way; the mixture was stirred at room temperature for 60
minutes and concentrated in vacuum to remove the solvent; 0.8mL of ethanol and 10%
sodium carbonate solution (0.5mL) containing SPIAd (25.3mg, 0.11mmol) were
sequentially dosed in the residue, and then the pH of the mixed solution was adjusted to 9
with 10% sodium carbonate solution (0.3mL); the mixture was stirred at room temperature
to react 70 minutes, and then the reaction solution was diluted with 5mL of water and
extracted three times with DCM, 5mL each time; the organic layers were combined, dried
over anhydrous magnesium sulfate, and concentrated in vacuum, and the the residue was
subjected to silica gel column chromatography (washed with ethyl acetate solution
containing 0-10% of methanol), thus obtaining the labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib as a white solid (18.32mg, 19%).
[00216] Example 44
[00217] I(III)-SPIAd-Bz-5-Larotrectinib was prepared by a method similar to the
method in Example 43, and the white solidI(III)-SPIAd-Bz-5-Larotrectinib was obtained
with a yield of 19% (18mmol, 18mg).
[00218] Example 45
[00219] Preparation of labeled precursor I(III)-SPIAd-Piv-2-Larotrectinib
F F 0 0
N' O N 0 - ~~ ~ F3CCOO ~~~KJ
0 0 C 26H 30FIN 60 3:620.47 C 30H 3OF 7IN0 7: 846.50 1 - Piv-2-Larotrectinib I- Piv-TfAc-2-Larotrectinib FNCCOOCNO
N6 F F Ca0oylay 84.5 C HgFNg- 85.7 0 -. 1N- 0 F_0
F3CCOO- N H<~ 1 F 3CCOO N H-N
C 30H 30F 7INGO7:846.50 H C 39H 44FIN 607: 854.72 1- Piv-TfAc-2-Larotrectinib I(111-SPIAd -Pl-2-Larotrectinib
[00220] Trifluoroacetic anhydride (C 4 F 6 0 3 = 210.04, 1.511 C g/mL, 0.068mL,
0.489mmol, 102.75mg) and trifluoroacetic acid (CF 3COOH=114.02, 1.5351g/cm3,
0.18mL, 0.276g, 2.43mmol) were dosed in alOmL round-bottomed flask; urea-hydrogen
peroxide (1.e25mmol, 106mg) was then slowly dosed in a stirring way to react and release
heat and the temperature of the system was controlled below 30 °C; then,
I-Piv-2-Larotrectinib (155.12mg, 0.25mmol) was dosed, the reaction mixture was cooled
to about 0 °C in an ice-water bath, and then anhydrous sodium sulfate (41mg, 0.5mmol)
was slowly dosed in the mixture; then, the reaction mixture was heated to 40°C for 1 hour
to 6 hours, and after TLC detected that the raw material I-Piv-2-Larotrectinib was
completely reacted, the reaction solution was diluted with 2.5mL of water and extracted
three times with DCM, 5mL each time; the organic phases were combined, dried over
anhydrous magnesium sulfate, filtered and concentrated under reduced pressure; the residue was subjected to silica gel column chromatography (eluted with ethyl acetate solution containing 0-10% of methanol), thus obtaining intermediate
I-Piv-TfAc-2-Larotrectinib as a white solid (143.91mg, 68%).
[00221] Na2CO3 (98.58mg, 0.93mmol) and MeCN (0.52ml), SPIAd (39.1mg,
0.17mmol) were dosed in a l0mL round-bottomed flask, and the heterogeneous mixture
was cooled to 0 °C in an ice-water bath and stirred vigorously for 5 minutes until the
mixture becomes milky white suspension. Intermediate I-Piv-TfAc-2-Larotrectinib
(143.91mg, 0.17 mmol) was dosed in the above vigorously stirred mixture at once, the
obtained mixture was continuously stirred at 0 °C to react for 2 hours, and the reaction
mixture gradually became a thick cream mixture. 10 mL of water was dosed, and the
obtained mixture was further stirred for 1 minute and then filtered to remove the fluffy
white suspended matter out of the beige biphase solution, the filter cake was washed twice
with water , 5 mL each time, the water needed to be vacuum dried every time the filter
cake was washed; the filter cake was then washed once with ether (10mL) and dried under
high vacuum, thus obtaining the labeled precursor I(III)-SPIAd-Piv-2-Larotrectinib as a
white solid (113.33mg, 78%, the total yield of 53% in two steps), with the m.p.of 100 °C
(decomposed).
[00222] Example 46
[00223] I(III)-SPIAd-Piv-5-Larotrectinib was prepared by a method similar to the
method in Example 45, and the white solid I(III)-SPIAd-Piv-5-Larotrectinib was obtained
with a yield of 78% (113mg - the total yield of 53% in two steps).
[00224] Example 47
[00225] Preparation of labeled precursor I(III)-SPIAd-Ac-2-Larotrectinib
F F 0 -. 0
-N OA C / 'CH 3 / N -N OA
SNF3CCOO N N§ H3
0 0 C 23H 24FINS0 3:578.39 C 27H 24F 7 1N07: 804.42 1 - Ac-2-Larotrectinib I - Ac-TfAc-2-Larotrectinib
F F 0 0 -0
F3CCOO-I1 \j-3N ~ N'N O CO C NN OAC H/OAc F 3CCOO N N H H N H
C27H 24F 71NO07: 804.42 H C 36H 38FIN 6O 7:812.64 I -Ac-TfAc-2-Larotrectinib |(Ill)-SPIAd -Ac -2- Larotrectinib
[00226] Trifluoroacetic anhydride (0.068mL, 0.489mmol, 102.75mg),
trifluoroacetic acid (0.18mL, 0.276g, 2.43mmol), and 0.18mL of chloroform were dosed
in a 2mL round-bottomed flask; Oxone(136.36mg,0.225mmol) was then slowly dosed in a
stirring way; then, I-Ac-2-Larotrectinib (127.25mg - 0.22mmol) was dosed, the reaction
mixture was cooled to about 0 °C in an ice-water bath, and then anhydrous magnesium
sulfate (60mg, 0.5mmol) was slowly dosed in the mixture; then, the reaction mixture
reacted at room temperature of 25 °C for 6 hours, and after TLC detected that the raw
material I-Ac-2-Larotrectinib was completely reacted, the reaction solution was diluted
with 3mL of ice water and extracted three times with DCM, 5mL each time; the organic
phases were combined and washed three times with saline solution, 2mL each time; the
organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure; the residue was subjected to silica gel column chromatography
(eluted with ethyl acetate solution containing 0-10% of methanol), thus obtaining
intermediate I-Ac-TfAc-2-Larotrectinib as a light yellow solid (114.68mg - 0.143mmol,
64.8%).
[00227] NaHCO3 (78.12mg, 0.93mmol), acetone (0.52ml), and SPIAd (39.1mg,
0.17mmol) were dosed in a 2mL round-bottomed flask, and the heterogeneous mixture was cooled to 0 °C in an ice-water bath and stirred vigorously for 5 minutes until the mixture becomes milky white suspension. Intermediate I-Ac-TfAc-2-Larotrectinib
(143.91mg 0.17mmol) was dosed in the above vigorously stirred mixture at once, the
obtained mixture was continuously stirred at 0 °C to react for 2 hours, and the reaction
mixture gradually became yellow; TLC tracked the reaction until the raw material was
completely converted; the insoluble matter was filtered off, and the reaction flask was
washed three times with dichloromethane, 0.12 mL each time, the insoluble matter was
rinsed with the washing liquid, and the yellow dichloromethane liquid was collected. The
collected liquid was concentrated under reduced pressure (at 20 °C) evaporated to remove
dichloromethane, and then dried for 1 hour under high vacuum, thus obtaining the labeled
precursor I(III)-SPIAd-Ac-2-Larotrectinib as a yellow solid (138.15mg, 46.6%).
[00228] Example 48
[00229] I(III)-SPIAd-Ac-5-Larotrectinib was prepared by a method similar to the
method in Example 47, and the white solid I(III)-SPIAd-Ac-5-Larotrectinib was obtained
with a yield of 46% (138mmol).
[00230] Example 49
[00231] Preparation of labeled precursor I(III)-SPIAd-Tf-2-Larotrectinib
F F 0 0 NN O\ CN OAC OA 5o N- CF3
NaN F3 CCOO NN3FN aF 0 0 C 23H 21F 4 1N 6 03:632.36 C 27H 23CIFIN 07: 838.86 1 -Tf-2-Larotrectinib I - Tf-TfAc-2-Larotrectinib
0~oI~0- 0C N'N O C O NN OA F3CCOO- N N F3 H CCOO F3 'HO
C27H 21F1 0lN 607: 858.39 H C36H 3 F4 1NO07: 866.61 1 -Tf-TfAc-2-Larotrectinib |(Ill)-SPIAd -Tf 2-Larotrectinib
[00232] Trifluoroacetic anhydride (0.068mL, 0.489mmol, 102.75mg),
trifluoroacetic acid (0.18mL, 0.276g, 2.43mmol), and 0.18mL of chloroform were dosed
in a 2mL round-bottomed flask; Oxone(136.36mg,0.225mmol) was then slowly dosed in a
stirring way; then, I-Tf-2-Larotrectinib (139.12mg - 0.22mmol) was dosed, the reaction
mixture was cooled to about 0 °C in an ice-water bath, and then anhydrous magnesium
sulfate (60mg, 0.5mmol) was slowly dosed in the mixture; then, the reaction mixture
reacted at room temperature of 25 °C for 6 hours, and after TLC detected that the raw
material I-Tf-2-Larotrectinib was completely reacted, the reaction solution was diluted
with 3mL of ice water and extracted three times with DCM, 5mL each time; the organic
phases were combined and washed three times with brine, 2mL each time; the organic
phase was dried over anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure; the residue was subjected to silica gel column chromatography (eluted
with ethyl acetate solution containing 0-10% of methanol), thus obtaining intermediate
I-Tf-TfAc-2-Larotrectinib as a light yellow solid (117.46mg - 0.137mmol, 62.2%).
[00233] K2C03 (128.34mg, 0.93mmol), methanol (0.52ml), and SPIAd (39.1mg,
0.17mmol) were dosed in a 2mL round-bottomed flask, and the heterogeneous mixture
was cooled to 0 °C in an ice-water bath and stirred vigorously for 5 minutes until the
mixture becomes milky white suspension. Intermediate I-Tf-TfAc-2-Larotrectinib
(117.46mg - 0.137mmol) was dosed in the above vigorously stirred mixture at once, the
obtained mixture was continuously stirred at 0 °C to react for 2 hours, and the reaction mixture gradually became yellow; TLC tracked the reaction until the raw material was completely converted; the insoluble matter was filtered off, and the reaction flask was washed three times with dichloromethane, 0.12 mL each time, the insoluble matter was rinsed with the washing liquid, and the yellow dichloromethane liquid was collected. The collected liquid was concentrated under reduced pressure (at 20 °C) evaporated to remove dichloromethane, and then dried for 1 hour under high vacuum, thus obtaining the labeled precursor I(III)-SPIAd-Tf-2-Larotrectinib as a yellow solid (53.9mg, 45.4%).
[00234] Example 50
[00235] I(III)-SPIAd-Tf-5-Larotrectinib was prepared by a method similar to the
method in Example 49, and the white solid I(III)-SPIAd-Tf-5-Larotrectinib was obtained
with a yield of 46% (54mg).
[00236] Example 51
[00237] Preparation of labeled precursor I(III)-SPIAd-CAc-2-Larotrectinib
/N OOCCH 2 CI N -N OOCCH 2 CI F3 CCOO-I 1 N F 3 CCOO N; N HN-W
0 0 C 23H2 3CIFIN0 3: 612.83 C 27H 23CIFIN 07:838.86 I -CAc-2-Larotrectinib I - CAc-TfAc-2-Larotrectinib
/N'N OOCCH 2CI O0' OOCCH 2CI F3CCo'aNHNH FCCOO N N H H O N0 HN
C27H 23CIFIN 607: 838.86 H C 3SH 37CIFIN 6O: 847.08 1- CAc-TfAc-2-Larotrectinib |(Ill)-SPIAd - CAc -2-Larotrectinib
[00238] 0.3mL of trifluoroacetic acid, trifluoroacetic anhydride (0.9mL), oxone
(H3K5018S4 = 614.76, 101.44mg, 0.165mmol), and 0.13mL of chloroform were dosed in
a 2mL reactor in a stirring way, the obtained solution was stirred vigorously at room
temperature, and I-CAc-2-Larotrectinib (67.41mg, 0.11mmol) was then dosed in the uniform solution; the obtained mixture was cooled to 0 °C; anhydrous sodium acetate
(0.53g, 6.45mmol) was slowly dosed in the vigorously stirred mixture; then, the mixture
was heated to 40 °C and vigorously stirred to react for 2 hours, and TLC tracked the
reaction until the raw material was completely converted; the mixture was cooled to room
temperature, diluted with 2 mL of water, and extracted three times with dichloromethane,
3ml each time; the organic phases were combined and extracted, then washed three times
with saturated brine, 3ml each time, dried with anhydrous sodium sulfate, filtered, and
concentrated; the residue was washed with n-heptane/ethyl acetate and filtered, thus
obtaining a yellow solid I-CAc-TfAc -2-Larotrectinib (57.12mg, 0.068mmol, 61.9%).
[00239] KHC03 (93mg, 0.93mmol), ethanol (0.52ml), and SPIAd (39.1mg,
0.17mmol) were dosed in a 2mL reactor, and the heterogeneous mixture was cooled to 0
°C in an ice-water bath and stirred vigorously for 5 minutes until the mixture becomes
milky white suspension. Intermediate I-CAc-TfAc-2-Larotrectinib (57.12mg, 0.068 mmol)
was dosed in the above vigorously stirred mixture at once, the obtained mixture was
continuously stirred at 0 °C to react for 2 hours, and the reaction mixture gradually
became yellow; TLC tracked the reaction until the raw material was completely converted;
the insoluble matter was filtered off, and the reaction flask was washed three times with
dichloromethane, 0.12 mL each time, the insoluble matter was rinsed with the washing
liquid, and the yellow dichloromethane liquid was collected. The collected liquid was
concentrated under reduced pressure (at 20 °C) evaporated to remove dichloromethane,
and then dried for 1 hour under high vacuum, thus obtaining the labeled precursor
I(III)-SPIAd-CAc-2-Larotrectinib as a yellow solid (26.84mg, 46.6%).
[00240] Example 52
[00241] I(III)-SPIAd-CAc-5-Larotrectinib was prepared by a method similar to the
method in Example 51, and the white solid I(III)-SPIAd-CAc-5-Larotrectinib was obtained with a yield of 46% (138mmol).
[00242] Example 53
[00243] Preparation of labeled precursor I(III)-SPIAd-DCAc-2-Larotrectinib
N'N OOCCHC1 2 / N-N OOCCHC1 2 / ;-.O
N N FCCOO N 64H 2 N2 7 H2 2 CN 2 F 71N 6 0 7
C 23 H 22 C12FIN 6 0 3 : 647.27 C27H22ClFylNOy: 873.30 1 - DCAc-2-Larotrectinib I - DCAc-TfAc-2-Larotrectinib
Ox N'.N OOCCHC1 2 H NN OOCCHC 2
F3CCOO N ; N H
C27H 22CI 2F 71N 607:873.30 CaH 3 36CI 2FIN 607:881.52 I - DCAc-TfAc-2-Larotrectinib H |(Ill)-SPIAd - DCAc-2-Larotrectinib
[00244] 0.3mL of trifluoroacetic acid, trifluoroacetic anhydride (0.9mL), oxone
(H 3 K 5 0 1 8 4 = 614.76, 101.44mg 0.165mmol), and 0.l3mL of chloroform were dosed in a
2mL reactor in a stirring way, the obtained solution was stirred vigorously at room
temperature, and I-DCAc-2-Larotrectinib(71.2mg - 0.11mmol) was then dosed in the
uniform solution; the obtained mixture was cooled to 0 °C; anhydrous sodium acetate
(0.53g, 6.45mmol) was slowly dosed in the vigorously stirred mixture; then, the mixture
was heated to 40 °C and vigorously stirred to react for 2 hours, and TLC tracked the
reaction until the raw material was completely converted; the mixture was cooled to room
temperature, diluted with 2 mL of water, and extracted three times with dichloromethane,
3ml each time; the organic phases were combined and extracted, then washed three times
with saturated brine, 3ml each time, dried with anhydrous sodium sulfate, filtered, and
concentrated; the residue was washed with N-heptane ethyl acetate and filtered, thus
obtaining a yellow solid I-DCAc-TfAc-2-Larotrectinib (65.32mg, 0.075mmol, 68%).
[00245] 10% sodium carbonate aqueous solution (w/v.0.75mL, 0.33M) containing
auxiliary acid adamantane (SPI-Adaman, 0.Immol, 23mg) and ethanol (1mL) were dosed
in a 2mL reaction flask, and then I -DCAc-TfAc-2-Larotrectinib (0.096mmol, 84.53mg)
was dosed quickly; the reaction mixture was stirred vigorously for 0.5 hour at room
temperature, and TLC tracked the reaction until the raw material was completely
converted; the reaction mixture was diluted with 2mL of water, and extracted three times
with dichloromethane, 3ml each time; the organic extract phases were combined, dried
with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the
residue was subjected to silica gel column chromatography and eluted with
n-heptane/ethyl acetate=10/1, thus obtaining the labeled precursor
I(III)-SPIAd-DCAc-2-Larotrectinib as a white solid (43.16mg, 46.8%, the total yield of
46.8% in two steps).
[00246] Example 54
[00247] I(III)-SPIAd-DCAc-5-Larotrectinib was prepared by a method similar to
the method in Example 53, and the white solid I(III)-SPIAd-DCAc-5-Larotrectinib was
obtained with a yield of 78% (43mg 47%, the total yield of 46.8% in two steps).
[00248] Example 55
[00249] Preparation of labeled precursor I(III)-SPIAd-Moc-2-Larotrectinib
F F 0 0 N'N OA O.-N O
N6 N HN FCCOO N
C 23H 24FINS0 4:594.39 C 2 7 H4 F 7 1N 6OS: 842.66 1 - Moc-2-Larotrectinib I - Moc-TfAc-2-Larotrectinib
F F 0 0
F3CO 1N' N OJ O N'O F 3CCOO N N H HN N
0 ""H 0
C27H 40FylNGO: 842.66 H C3SH 38FINSO 8 : 828.64 1 -Moc-TfAc-2-Larotrectinib I(III)-SPIAd -Moc -2-Larotrectinib
[00250] 0.36 mL of trifluoroacetic acid and 0.18 mL of chloroform were dosed in a
2 mL reactor; I-Moc-2-Larotrectinib (89.16mg, 0.15mmol) and oxone (110.66mg,
0.18mmol) were dosed in a stirring way; the mixture was heated to 45 °C and stirred to
react for 3 hours; then, the reaction mixture was concentrated under reduced pressure to
remove the solvent; 1.2 mL of ethanol and 0.68 mL of SPIAd (34.5 mg, 0.15 mmol)
dissolved in 10% sodium carbonate solution were dosed in the residue and the pH of the
mixture was adjusted to 12 with the 10% sodium carbonate solution. The mixture was
stirred at 50°C for 3 hours, and TLC tracked the reaction until the raw material was
completely converted; the reactant was diluted with 3mL of water, and extracted three
times with DCM, 5 mL each time; the organic phases were combined, dried over
magnesium sulfate, and concentrated under reduced pressure; and the residue was
subjected to silica gel column chromatography (eluted with 0-40% ethyl acetate-petroleum
ether solution), thus obtaining the labeled precursor I(III)-SPIAd-Moc-2-Larotrectinib as a
white solid (38.91mg, 31.3%).
[00251] Example 56
[00252] I(III)-SPIAd-Moc-5-Larotrectinib was prepared by a method similar to the
method in Example 55, and the white solid I(III)-SPIAd-Moc-5-Larotrectinib was
obtained with a yield of 31% (39mg).
[00253] Example 57
[00254] Preparation of labeled precursor I(III)-SPIAd-Eoc-2-Larotrectinib
F F 0 0
0 0
C 24H 26FINS0 4 :608.41 C 28H 2 6F 7lN 609:834.44 I - Eoc-2-Larotrectinib I - Eoc-TfAc-2-Larotrectinib
F F 0 0 / O NNO O NO F3CCOO-I O 'C 0 F3CCOO N N HN,, , N N
C28H 2SF 7 N 6OS: 834.44 H C 37H40FIN 6Os:842.66 I - Eoc-TfAc-2-Larotrectinib I(III)-SPIAd -Eoc - 2-Larotrectinib
[00255] 0.36 mL of trifluoroacetic acid and 0.18 mL of chloroform were dosed in a
2 mL reactor; I-Eoc-2-Larotrectinib (91.26mg 0.15 mmol) and
Oxone(110.66mg,0.18mmol) were dosed in a stirring way; the mixture was heated to 37
°C and stirred to react for 3 hours; then, the reaction mixture was concentrated under
reduced pressure to remove the solvent; 1.2 mL of ethanol and 0.68 mL of SPIAd (34.5
mg, 0.15 mmol) dissolved in 10% sodium carbonate solution were dosed in the residue,
and the pH of the mixture was adjusted to 11 with the 10% sodium carbonate solution. The
mixture was stirred at 60°C for 2 hours and TLC tracked the reaction until the raw
material was completely converted; the reactant was diluted with 3mL of water and
extracted three times with DCM, 5 mL each time; the organic phases were combined,
dried over magnesium sulfate, and concentrated under reduced pressure; and the residue
was subjected to silica gel column chromatography (eluted with 0-40% ethyl
acetate-petroleum ether solution), thus obtaining the labeled precursor
I(III)-SPIAd-Eoc-2-Larotrectinib as a white solid (33.57mg, 33.2%).
[00256] Example 58
[00257] I(III)-SPIAd-Eoc-5-Larotrectinib was prepared by a method similar to the
method in Example 57, and the white solid I(III)-SPIAd-Eoc-5-Larotrectinib was obtained with a yield of 33% (34mg).
[00258] Example 59
[00259] Preparation of labeled precursor I(III)-SPIAd-Boc-2-Larotrectinib
/x N OBoc 0 NN OBoc NI H 0 N HN Hi 0 N HN N
00 C 26H3oFINGO4 : 636.47 H C3 9H 44FINGO0: 870.72 I - Boc-2-Larotrectinib I(III)-SPIAd - Boc-2-Larotrectinib
[00260] 0.8mL of dichloromethane was dosed in a 2mL reactor, and
I-Boc-2-Larotrectinib (89.11mg, 0.14mmol) and mCPBA (40mg, 0.18mmol) were then
dosed in a stirring way; the mixture was stirred vigorously at room temperature and
reacted for 1 hour to 2 hours, TLC tracked the reaction until the raw material was
completely reacted, and the obtained material was for later use.
[00261] KOH = 56.1 (47.12mg, 0.84mmol), dichloromethane (0.47ml), and SPIAd
(39.1mg, 0.17mmol) were dosed in a 2mL reactor, and the heterogeneous mixture was
cooled to 0 °C in an ice-water bath and stirred vigorously for 5 minutes until the mixture
becomes milky white suspension (pH12). The material obtained above for later use was
dosed in the above vigorously stirred mixture at once, the obtained mixture was
continuously stirred at 0 °C to react for 2 hours, and the reaction mixture gradually
became yellow; TLC tracked the reaction until the raw material was completely converted;
the insoluble matter was filtered off, and the reaction flask was washed three times with
dichloromethane, 0.12 mL each time, the insoluble matter was rinsed with the washing
liquid, and the yellow dichloromethane liquid was collected. The collected liquid was
concentrated under reduced pressure (at 20 °C) evaporated to remove dichloromethane,
and then dried for 1 hour under high vacuum, thus obtaining the labeled precursor
I(III)-SPIAd-Boc-2-Larotrectinib as a yellow solid (49.74mg, 40.8%) with the m.p.of 88.6
°C (decomposed).
[00262] Example 60
[00263] I(III)-SPIAd-Boc-5-Larotrectinib was prepared by a method similar to the
method in Example 59, and the white solid I(III)-SPIAd-Boc-5-Larotrectinib was obtained
with a yield of 40% (49mg).
[00264] Example 61
[00265] Preparation of labeled precursor I(III)-SPIAd-Troc-2-Larotrectinib
/ /CC13-- N O CCI 3 NF3CCOO N N0
0 0 C2 4 H2 3 C1 3FIN 6 04 :711.74 C 2 gH2 3C 3F7 1N 60 8 :937.77 I -Troc-2-Larotrectinib I - Troc-TfAc-2-Larotrectinlib
F N O CCl3
F 3 CCOO- 1 0H F3 CCOOZ N6 O H, NO HN-( O'
C28H 23 CI3 F7 IN6 O8 :937.77 H C3 7H 37 C13FIN 6 08 :945.99 I - Troc-TfAc-2-Larotrectinib I(III)-SPAd -Troc-2-Larotrectinib
[00266] 0.36 mL of trifluoroacetic acid and 0.18 mL of chloroform were dosed in a
2 mL reactor; I-Troc-2-Larotrectinib (106.76mg 0.15 mmol) and
Oxone(110.66mg,0.18mmol) were dosed in a stirring way; the mixture was heated to 70
°C and stirred to react for 2 hours; then, the reaction mixture was concentrated under
reduced pressure to remove the solvent; 1.2 mL of ethanol and 0.68mL of SPIAd (34.5mg,
0.15mmol) dissolved in 10% sodium carbonate solution were dosed in the residue, and the
pH of the mixture was adjusted to 9 with the 10% sodium carbonate solution. The mixture
was stirred at room temperature for 70 minutes; TLC tracked the reaction until the raw
material was completely converted; the reactant was diluted with 3mL of water and
extracted three times with DCM, 5 mL each time; the organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure; and the residue was subjected to silica gel column chromatography (eluted with 0-40% ethyl acetate-petroleum ether solution), thus obtaining the labeled precursor
I(III)-SPIAd-Troc-2-Larotrectinib as a white solid (53.92mg, 38%).
[00267] Example 62
[00268] I(III)-SPIAd-Troc-5-Larotrectinib was prepared by a method similar to the
method in Example 61, and the white solid I(III)-SPIAd-Troc-5-Larotrectinib was
obtained with a yield of 38% (53mg).
[00269] Example 63
[00270] Preparation of labeled precursor I(III)-SPIAd-Teoc-2-Larotrectinib
F 0 F
/ _N O/O IF 3CCOO-~ 0\
K~iN N S ~ F 3CCOO N N
0 O C27 H34 FIN 604 Si:680.59 C31 H34 F 7IN 6 OSi:906.63 I -Teoc-2-Larotractinib I - Teoc-TfAc-2-Larotrectinib
F3CCO 0 H F3CCOO HNFa 0 NN H HN N
0 H C 31 H3 6F7 IN60 7 Si:892.64 H C4eH4SFIN 6 0 Si:914.85 I - Teoc-TfAc-2-Larotrnctinib |(III)-SPIAd -Teoc-2-Larotrectinib
[00271] Trifluoroacetic anhydride (0.068mL, 0.489mmol, 102.75mg),
trifluoroacetic acid (0.18mL, 0.276g, 2.43mmol), and 0.18mL of chloroform were dosed
in a 2mL round-bottomed flask; Oxone(136.36mg,0.225mmol) was then slowly dosed in a
stirring way; then, I-Teoc-2-Larotrectinib (147.73mg - 0.22mmol) was dosed, the reaction
mixture was cooled to about 0 °C in an ice-water bath, and then anhydrous magnesium
sulfate (60mg, 0.5mmol) was slowly dosed in the mixture; then, the reaction mixture reacted at room temperature of 25 °C for 6 hours, and after TLC detected that the raw material I-Tf-2-Larotrectinib was completely reacted, the reaction solution was diluted with 3mL of ice water and extracted three times with DCM, 5mL each time; the organic phases were combined and washed three times with brine, 2mL each time; the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure; the residue was subjected to silica gel column chromatography (eluted with ethyl acetate solution containing 0-10% of methanol), thus obtaining intermediate
I-teoc-TfAc-2-Larotrectinib as a light yellow solid (153.96mg, 0.173mmol, 78.4%).
[00272] KOH(52.08mg, 0.93mmol), MeCN(0.52ml) and SPIAd(39.1mg, 0.17mmol)
were dosed in a 1I0mL round-bottomed flask, and the heterogeneous mixture was cooled to
°C in an ice-water bath and stirred vigorously for 5 minutes until the mixture becomes
milky white suspension. Intermediate I-Teoc-TfAc-2-Larotrectinib (143.91mg, 0.17mmol)
was dosed in the above vigorously stirred mixture at once, the obtained mixture was
continuously stirred at 0 °C to react for 2 hours, and the reaction mixture gradually
became a thick cream mixture. 10 mL of water was dosed, and the obtained mixture was
further stirred for 1 minute and then filtered to remove the fluffy white suspended matter
out of the beige biphase solution, the filter cake was washed twice with water, 5mL each
time, the water needed to be vacuum dried every time the filter cake was washed; the filter
cake was then washed once with ether (10mL) and dried under high vacuum, thus
obtaining the labeled precursor I(III)-SPIAd-Teoc-2-Larotrectinib as a white solid
(121.31mg, 78%, the total yield of 61.1% in two steps), with the m.p.of 115 °C
(decomposed).
[00273] Example 64
[00274] I(III)-SPIAd-Teoc-5-Larotrectinib was prepared by a method similar to the
method in Example 63, and the white solid I(III)-SPIAd-Teoc-5-Larotrectinib was obtained (121mg, 78%, the total yield of 61% in two steps).
[00275] Example 65
[00276] Preparation of labeled precursor I(III)-SPIAd-TBS-2-Larotrectinib
N-N OTBS N OTBS - ~F 3CCOO...I
0 C 27H 36FIN0 2Si:650.61 C 31H 3 6F 71N O0Si: 6 876.64 1 -TBS-2-Larotrectinib I - TBS-TfAc-2-Larotrectinib
'N OTBS 0 N OTBS FCN FaCCOO- NNH O H I F3CCOO NNNH~'O~ I K~ N N
C 31H 3 F 71NG0 6Si: 876.64 H C4HSOFINGOGSI: 884.86 1 -TBS-TfAc-2-Larotrectinib |(Ill)-SPIAd -TBS - 2-Larotrectinib
[00277] 0.39mL of trifluoroacetic acid and 0.13mL of acetonitrile were dosed in a
mL reactor and the mixture was stirred and cooled to 0 °C; Oxone (100mg, 0.165mmol)
and I-TBS-2-Larotrectinib (70.2mg, 0.11mmol) were sequentially dosed in the mixture;
then, the mixture was stirred at 0 °C to react for 30 minutes; 0.8mL of ethanol and 0.5mL
of SPIAd (25.3mg, 0.11mmol) dissolved in 10% sodium carbonate solution were dosed in
the residue, and the pH of the mixture was adjusted to 9 with 0.3mL of the 10% sodium
carbonate solution. The mixture was stirred at room temperature for 70 minutes and then
diluted with 5mL of water and extracted three times with DCM, 5mL each time; the
organic phases were combined, dried over magnesium sulfate, and concentrated under
reduced pressure; and the residue was subjected to silica gel column chromatography
(eluted with ethyl acetate solution containing 0-10% of methanol), thus obtaining the
labeled precursor I(III)-SPIAd-TBS-2-Larotrectinib as a white solid (17.52mg, 18%).
[00278] Example 66
[00279] I(III)-SPIAd-TBS-5-Larotrectinib was prepared by a method similar to the
method in Example 65, and the white solid I(III)-SPIAd-TBS-5-Larotrectinib was
obtained (38mg, 30%).
[00280] Example 67
[00281] Another preparation method of labeled precursor
I(III)-SPIAd-TBS-2-Larotrectinib
N6H H NN N
N H"'H 0 C 27H 36FIN 602Si:650.61 H C 40H 50FIN 6 06Si: 884.86 S-TBS-2-Larotrectinib I(Ill)-SPIAd -TBS - 2-Larotrectinib
[00282] 0.8mL of dichloromethane was dosed in a 2mL reactor, and
I-TBS-2-Larotrectinib (89.11mg, 0.14mmol) and mCPBA (40mg, 0.18mmol) were then
dosed in a stirring way; the mixture was stirred vigorously at room temperature and
reacted for 1 hour to 2 hours, TLC tracked the reaction until the raw material was
completely reacted, and the obtained material was for later use.
[00283] KOH = 56.1 (47.12mg, 0.84mmol), dichloromethane (0.47ml), and SPIAd
(39.1mg, 0.17mmol) were dosed in a 2mL reactor, and the heterogeneous mixture was
cooled to 0 °C in an ice-water bath and stirred vigorously for 5 minutes until the mixture
becomes milky white suspension (pH12). The material obtained above for later use was
dosed in the above vigorously stirred mixture at once, the obtained mixture was
continuously stirred at 0 °C to react for 2 hours, and the reaction mixture gradually
became yellow; TLC tracked the reaction until the raw material was completely converted;
the insoluble matter was filtered off, and the reaction flask was washed three times with
dichloromethane, 0.12 mL each time, the insoluble matter was rinsed with the washing liquid, and the yellow dichloromethane liquid was collected. The collected liquid was concentrated under reduced pressure (at 20 °C) evaporated to remove dichloromethane, and then dried for 1 hour under high vacuum, thus obtaining the labeled precursor
I(III)-SPIAd-TBS-2-Larotrectinib as a yellow solid (38.16mg, 30.8% in total).
[00284] Example 68
[00285] I(III)-SPIAd-TBS-5-Larotrectinib was prepared by a method similar to the
method in Example 67, and the white solid I(III)-SPIAd-TBS-5-Larotrectinib was
obtained (38mg, 30%).
[00286] Example 69
[00287] Preparation of labeled precursor I(III)-SPIAd-TBDPS-2-Larotrectinib
N N6 0. FaCCOO N N
0 0 C 37H4 0FING02Si:774.75 C4 1H 4WFylN 60 6S:1000.79 S-TBDPS-2-Larotrectinib I - TBDPS-TfAc-2-Larotrectinib
F3 CCON'N OTBDPS 0 /N OTBDPS
F 3 CCOO HN N N
C41H 40FylNGOSSi: 1000.79 H C 50H54FINSO$iS: 1009.01 1 - TBDPS-TfAc-2-Larotrectinib |(Ill)-SPIAd -TBDPS - 2-Larotrectinib
[00288] 0.53 mL of trifluoroacetic acid, 0.18mL of chloroform and magnesium
chloride (MgCl2, 0.95mg, 0.Olmmol) were dosed in a 2 mL reactor;
I-TBDPS-2-Larotrectinib (116.22mg, 0.15 mmol) and Oxone (H 3 K5 0 1 8 S 4 = 614.76,
136.36mg, 0.225mmol) were dosed in a stirring way; the mixture was heated to 80 °C and
stirred to react for 3 hours, and TLC tracked the reaction until the raw material was
completely reacted; the reaction mixture was filtered to remove the solid and then
concentrated under reduced pressure to remove the solvent; 1.2mL of ethanol and 0.68 mL of SPIAd (34.5mg, 0.15mmol) dissolved in 10% sodium carbonate solution were dosed in the residue, and the pH of the mixture was adjusted to 9 with 0.41mL of the 10% sodium carbonate solution. The mixture was stirred at room temperature for 70 minutes; TLC tracked the reaction till the end of the reaction; the reactant was diluted with 3mL of water, and extracted three times with DCM, 5 mL each time; the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure; and the residue was subjected to silica gel column chromatography (eluted with 0-40% ethyl acetate-petroleum ether solution), thus obtaining the labeled precursor
I(III)-SPIAd-PMP-2-Larotrectinib as a white solid (52.97mg, 35%).
[00289] Example 70
[00290] I(III)-SPIAd-TBS-5-Larotrectinib was prepared by a method similar to the
method in Example 69, and the white solid I(III)-SPIAd-TBS-5-Larotrectinib was
obtained (53mg, 35%).
[00291] Example 71
[00292] Preparation of labeled precursor I(III)-SPIAd-TIPS-2-Larotrectinib
KiiiiYN /N.--N OTIPS F3 CCOO- 1 N....N OTIPS
N N6 F,~CCOO HN Khi N HN_, N6
0 0 C3 0H4FINGO 2Si:692.69 Ca4HaF7 NGOoSi: 918.72 1 - TIPS-2-Larotrectinib I - TIPS-TfAc-2-Larotrectinib
.. N OTIPS O N.. N OTIPS F3 CCOO-~ H
d TP CCOO F3 N _ - N H,-_O H KQIJNN N
C 34HaF 7IN 6O 6Si: 918.72 H C43HSGFINNO0Si: 926.94 1 -TIPS-TfAc-2-Larotrectinib |(Ill)-SPIAd -TIPS - 2-Larotrectinib
[00293] 4mL of dichloromethane was dosed in a 2mL reactor and trifluoroacetic
anhydride (0.16mL, 0.24g, 1.14mmol), Oxone (67.63mg, 0.11mmol), 2,2,6,6-tetramethyl piperidine-oxide (TEMPO, 0.001mmol, 0.056mg), and anhydrous lithium chloride (LiCl,
0.42mg, 0.01mmol) were then dosed in a stirring way; the mixture was stirred well at
room temperature, and I-TIPS-2-Larotrectinib (86.33mg, 0.11mmol) was then dosed; the
resulting mixture was reacted at room temperature for 2 hours, and TLC tracked the
reaction process; after the raw material disappeared, the solid was removed by filtration;
then, the organic phase was concentrated, and the residue was separated by silica gel
column chromatography (eluted with developing solvent: 0-50% ethyl acetate-n-heptane,
v/v); the target product eluate was collected and concentrated, thus obtaining a colorless
solid I-TIPS-TfAc-2-Larotrectinib (63.67mg, 0.069 mmol, 63%).
[00294] 10% sodium carbonate aqueous solution (w/v.0.75mL, 0.33M) containing
auxiliary acid adamantane (SPI-Adaman, 0.1mmol, 23mg) and ethanol (1mL) were dosed
in a 2mL reaction flask, and then I-TIPS-TfAc-2-Larotrectinib (0.069mmol, 63.67mg) was
dosed quickly; the reaction mixture was stirred vigorously for 4 hour at room temperature,
and TLC tracked the reaction until the raw material was completely converted; the reacant
was diluted with 3mL of water, and extracted three times with DCM, 5ml each time; the
organic phases were combined, dried with anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure; the residue was subjected to silica gel column
chromatography (eluted with developing solvent: 0- 5 0 % ethyl acetate-petroleum ether,
v/v); the target product eluate was collected and concentrated, thus obtaining labeled
precursor I(III)-SPIAd-TIPS-2-Larotrectinib as a white solid (42.82mg, the total yield of
42% in two steps).
[00295] Example 72
[00296] I(III)-SPIAd-TIPS-5-Larotrectinib was prepared by a method similar to the
method in Example 71, and the white solid I(III)-SPIAd-TIPS-5-Larotrectinib was
obtained (42mg, the total yield of 42% in two steps).
[00297] Example 73
[00298] Preparation of labeled precursor I(III)-SPIAd-PMB-2-Larotrectinib
F OMe F P' OMe a O~e
N N FaCCOO O N6
C 3 3 H3 0F7 1N 60 7 :882.53 C29H 30FIN 603:656.50 I - PMB-TfAc-2-Larotrectinib I - PMB-2-Larotrectinib
F F OMe N OMe N 0 0 5;1N-N 0
F3CCOO _ H N N HN_( 0 H 0 C3 3H 3 0F 7 IN 60 7 :882.53 H C 42H 44FIN 60 7:890.75 I - PMB-TfAc-2-Larotrectinib I(III)-SPIAd -PMB-2-Larotrectinib
[00299] 0.53mL of trifluoroacetic acid and 0.18mL of chloroform were dosed in a 2
mL reactor; I-PMB-2-Larotrectinib (98.47mg, 0.15 mmol), sodium chloride (0.59mg,
0.Olmmol), and Oxone (H 3 K5 0 1 8 S 4 = 614.76, 138.32mg, 0.225mmol) were dosed in a
stirring way; the mixture was heated to 80 °C and stirred to react for 3 hours, and TLC
tracked the reaction until the raw material was completely reacted; the reaction mixture
was then concentrated under reduced pressure to remove the solvent; 1.2mL of ethanol
and 0.68 mL of SPIAd (34.5mg, 0.15mmol) dissolved in 10% sodium carbonate solution
were dosed in the residue, and the pH of the mixture was adjusted to 9 with 10% sodium
carbonate solution. The mixture was stirred at room temperature for 70 minutes; TLC
tracked the reaction till the end of the reaction; the reactant was diluted with 3mL of water,
and extracted three times with DCM, 5 mL each time; the organic phases were combined,
dried over anhydrous magnesium sulfate, concentrated under reduced pressure; and the
residue was subjected to silica gel column chromatography (eluted with 0-40% ethyl
acetate-petroleum ether solution), thus obtaining the labeled precursor
I(III)-SPIAd-PMB-2-Larotrectinib as a yellow solid (44.89mg, 33.6%).
[00300] Example 74
[00301] I(III)-SPIAd-PMB-5-Larotrectinib was prepared by a method similar to the method in Example 73, and the white solid I(III)-SPIAd-PMB-5-Larotrectinib was obtained (45mg, 34%).
[00302] Example 75
[00303] Preparation of labeled precursor I(III)-SPIAd-MOM-2-Larotrectinib
CCOO N> F 3 N N HN
0 0
C2 3 H26 FIN 6 03 :580.40 C 27 H26 F 7IN 60 7 :806.43 I -MOM-2-Larotrectinib I - MOM-TfAc-2-Larotrectinib
F3 CCOO NMH KiNN C27H26 F7IN6 0 7 :806.43 H C3 6H 40 FIN6 0 7 :814.65 I -MOM-TfAc-2-Larotrectinib I(III)-SPIAd - MOM-2-Larotrnctinib
[00304] 4mL of acetonitrile was dosed in a 2mL reactor and Oxone (H 3 K5 0 1 8 S 4 =
614.76, 67.63mg, 0.11mmol) and 0.05mL of acetone were then dosed in a stirring way; the
mixture was stirred well at room temperature; I-MOM-2-Larotrectinib(63.84mg
0.11mmol) was then dosed; the resulting mixture was heated to 60 °C and reacted for 2
hours and the reaction solution was then cooled to room temperature; trifluoroacetic
anhydride (0.16mL, 0.24g, 1.14mmol) was dosed dropwise, the resulting mixture reacted
at room temperature for 2 hours, and TLC tracked the reaction process; after the raw
material disappeared, the solid was removed by filtration; the residue was separated by
silica gel column chromatography (eluted with developing solvent: 0-50% ethyl
acetate-n-heptane, v/v); the target product eluate was collected and concentrated, thus
obtaining a yellow solid I-MOM-TfAc-2-Larotrectinib (48.79mg, 0.061 mmol, 55%).
[00305] 10% sodium carbonate aqueous solution (w/v.0.75mL, 0.33M) containing auxiliary acid adamantane (SPI-Adaman,0.1mmol,23mg) and ethanol (1mL) were dosed in a 2mL reaction flask, and then I-MOM-TfAc-2-Larotrectinib (0.061mmol,48.79mg) was dosed quickly; the reaction mixture was stirred vigorously for 3 hour at room temperature, and TLC tracked the reaction until the raw material was completely converted; the reacant was diluted with 3mL of water, and extracted three times with dichloromethane, 5ml each time; the organic extract phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the residue was subjected to silica gel column chromatography (eluted with developing solvent:
-50% ethyl acetate-petroleum ether, v/v); the target product eluate was collected and
concentrated, thus obtaining labeled precursor I(III)-SPIAd-MOM-2-Larotrectinib as a
white solid (38.53mg, the total yield of 43% in two steps).
[00306] Example 76
[00307] I(III)-SPIAd-MOM-5-Larotrectinib was prepared by a method similar to
the method in Example 75, and the white solid I(III)-SPIAd-MOM-5-Larotrectinib was
obtained (38mg, the total yield of 43% in two steps).
[00308] Example 77
[00309] Preparation of labeled precursor I(III)-SPIAd-MEM-2-Larotrectinib
/ N OMEM /- N OMEM F3CCOO- 1 N H
NN F 3CCOO NN
0 0 C 25 H3 OF1N 6 04 :624.46 C 29H 3 OF7 IN6 0S :850.49 1 -MEM-2-Larotrectinib I - MEM-TfAc-2-Larotrectinib
OMEM H N'N OMEM N'N F 3CCOO- H~)' F,~CCOO N HN H H O N N6
0 "H 0 C 29 H3 F7 IN 60 8 :850.49 H C3 8H 44FIN60S:858.71 I - MEM-TfAc-2-Larotrectinib |(Ill)-SPIAd - MEM-2-Larotrectinib
[00310] 0.4mL of acetonitrile was dosed in a 2mL reactor and Oxone (67.63mg
0.11mmol) and NaBr(0.011mmol,1.13mg) were then dosed in a stirring way; the mixture
was stirred well at room temperature; I-MEM-2-Larotrectinib(68.69mg - 0.11mmol) was
then dosed; the resulting mixture was heated to 60 °C and reacted for 2 hours and the
reaction solution was then cooled to room temperature; trifluoroacetic anhydride (0.16mL,
0.24g, 1.14mmol, 1.511 C g/mL) was dosed dropwise, the resulting mixture reacted at
room temperature for 2 hours, and TLC tracked the reaction process; after the raw material
disappeared, the solid was removed by filtration; the organic phase was concentrated and
the residue was then separated by silica gel column chromatography (eluted with
developing solvent: 0-50% ethyl acetate-n-heptane, v/v); the target product eluate was
collected and concentrated, thus obtaining a colorless solid I-MEM-TfAc-2-Larotrectinib
(52.39mg, 0.062mmol, 56%).
[00311] 10% sodium carbonate aqueous solution (w/v.0.75mL, 0.33M) containing
auxiliary acid adamantane (SPI-Adaman, 0.Immol, 23mg) and ethanol (1mL) were dosed
in a 2mL reaction flask, and then I-MEM-TfAc-2-Larotrectinib (0.062mmol, 52.39mg)
was dosed quickly; the reaction mixture was stirred vigorously for 4 hour at room
temperature, and TLC tracked the reaction until the raw material was completely
converted; the reaction mixture was diluted with 3mL of water, and extracted three times
with dichloromethane, 5ml each time; the organic extract phases were combined, dried
with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the residue was subjected to silica gel column chromatography (eluted with developing solvent: 0-50% ethyl acetate-petroleum ether, v/v); the target product eluate was collected and concentrated, thus obtaining labeled precursor I(III)-SPIAd-MEM-2-Larotrectinib as a white solid (30.23mg, the total yield of 32% in two steps).
[00312] Example 78
[00313] I(III)-SPIAd-MEM-5-Larotrectinib was prepared by a method similar to
the method in Example 77, and the white solid I(III)-SPIAd-MEM-5-Larotrectinib was
obtained (30mg, the total yield of 32% in two steps).
[00314] Example 79
[00315] Preparation of labeled precursor I(III)-SPIAd-SEM-2-Larotrectinib
N-N 0 O .N OSEM
N N 81w F3 CCOO NN 0 O C27 H36 FIN 6 03 Si:666.61 C31 H36 F7 IN6 0 7 Si:892.64 I -SEM-2-Larotrectinib I - SEM-TfAc-2-Larotrectinib
" 1 N OSEM 0 N...N OSEM F3 CCOO-_ 1 NH I F3CCOO N N H N
C 31H 36 F7 IN 6 07 Si:892.64 H C 40 HSOFIN 6 07 Si:900.86 I - SEM-TfAc-2-Larotrectinib |(Ill)-SPIAd - SEM-2-Larotrectinib
[00316] 0.13mL of acetonitrile, trifluoroacetic acid (0.39mL, 5.26mmol, 0.6g,
1.5351g/cm 3), and Oxone (100mg, 0.165mmol) were dosed in a 2mL reactor; the mixture
was cooled to 0 °C to 5 °C in an ice-water bath and stirred to react for 0.5 hour;
I-SEM-2-Larotrectinib (73.32mg, 0.11mmol) was slowly dosed dropwise to the vigorously
stirred mixture; the mixture was stirred and reacted at 0 to 5 °C for 1 hour, and the reaction
solution was diluted with ethanol (0.5mL); 10% sodium carbonate solution (0.1mL)
containing auxiliary acid adamantane (SPI-Adaman, 25.3mg, 0.11mmol) was then dosed quickly, and the pH of the mixed solution was adjusted to about 9 with 10% sodium carbonate solution (note: bubbles were generated in this step). The mixture was stirred at 0
°C to 5 °C for 3 hours and then diluted with 5mL of water, and extracted three times with
DCM, 5mL each time; the organic phases were combined, dried over magnesium sulfate,
and concentrated under reduced pressure; and the residue was subjected to silica gel
column chromatography (N-heptane/ethyl acetate=10/1), thus obtaining the labeled
precursor I(III)-SPIAd-SEM-2-Larotrectinib as a white solid (20.81mg, the total yield of
21% in two steps).
[00317] Example 80
[00318] I(III)-SPIAd-SEM-5-Larotrectinib was prepared by a method similar to the
method in Example 79, and the white solid I(III)-SPIAd-SEM-5-Larotrectinib was
obtained (20mg, the total yield of 21% in two steps).
[00319] Example 81
[00320] Preparation of labeled precursor I(III)-SPIAd-THP-2-Larotrectinib
NN 0-J F 3CCOO N'N N 0 0
N F3CCOO N N HN-, HN N
O 0 C 27 H 30FIN 6 O 3 Si:620.47 C39 H 44 FIN6 0 7 Si:854.72 I - THP-2-Larotrectinib I -TfAc- THP-2-Larotrectinib
F OF F N 00N
F 3CCOO N N H N
C 39H 44 FIN6 O 7 Si:854.72 H C39 H44 FIN6O7 Si:854.72 I-TfAc- THP-2-Larotrnctinib |(III)-SPIAd -THP-2-Larotrectinib
[00321] 0.13mL of dichloromethane and tert-butanol peroxide (tBuOOH, TBHP,
2.79g, 31mmol) were dosed in a 1mL reactor in a stirring way; I-THP-2-Larotrectinib
(68.25mg, 0.11mmol) was then dosed, and the resulting mixture was cooled to 0 °C in an
ice-water bath and stirred vigorously for 1 hour; TLC tracked the reaction until the raw
material was completely converted, and the obtained material was for later use.
[00322] KOH (47.12mg, 0.84mmol), dichloromethane (0.47ml), and SPIAd
(39.1mg, 0.17mmol) were dosed in a 2mL reactor, and the heterogeneous mixture was
cooled to 0 °C in an ice-water bath and stirred vigorously for 5 minutes until the mixture
becomes milky white suspension. The material obtained above for later use was dosed in
the above vigorously stirred mixture at once, the obtained mixture was continuously
stirred at 0 °C to react for 2 hours, and the reaction mixture gradually became yellow; TLC
tracked the reaction until the raw material was completely converted; the insoluble matter
was filtered off, and the reaction flask was washed three times with dichloromethane, 0.12
mL each time, the insoluble matter was rinsed with the washing liquid, and the yellow
dichloromethane liquid was collected. The collected liquid was concentrated under
reduced pressure (at 20 °C) evaporated to remove dichloromethane, and then dried for 1
hour under high vacuum, thus obtaining the labeled precursor
I(III)-SPIAd-THP-2-Larotrectinib as a yellow solid (27.08mg, 28.8%).
[00323] Example 82
[00324] I(III)-SPIAd-THP-5-Larotrectinib was prepared by a method similar to the
method in Example 81, and the white solid I(III)-SPIAd-THP-5-Larotrectinib was
obtained (27mg, 28%).
[00325] Example 83
[00326] Preparation of labeled precursor I(III)-SPIAd-EE-2-Larotrectinib
NN 0( ~N-N 0 N l-N N N NS FCCOO NN
0 0
C 25H 3 0FIN 6 03:608.46 C 29 H30 FIN 6 0 7 :834.49 I -EE-2-Larotrectinib I -TfAc- EE-2-Larotrectinib
F CCOO 3 N N6 H N N
C 29H30FIN 6 0 7:834.49 H C3 sH44FIN 6 07:842.71 I -TfAc- EE-2-Laratrectinib |(III)-SPIAd -EE-2-Larotractinib
[00327] 0.13mL of chloroform, 0.3mL of trifluoroacetic acid, trifluoroacetic
anhydride (0.9mL), Oxone (H 3 K5 0 18 S 4 = 614.76, 101.44mg, 0.165mmol), and
I-EE-2-Larotrectinib (71.2mg, 0.11mmol) were dosed in a 2mL reactor, the obtained
solution was cooled to 0 °C in an ice-water bath and stirred vigorously; anhydrous
potassium acetate (0.53g, 6.45mmol) was then slowly dosed in the mixture; the obtained
mixture was further stirred at 0 °C to 5 °C to react for 0.5 hour; the reaction solution was
then diluted with water and extracted with dichloromethane; the organic phases were
combined and extracted, then dried with anhydrous sodium sulfate, filtered, and
concentrated; the residue was washed with n-heptane/ethyl acetate and filtered, thus
obtaining a colorless solid I-EE-TfAc-2-Larotrectinib (52.24mg, 0.064 mmol, 58%).
[00328] 10% sodium carbonate aqueous solution (w/v.0.75mL, 0.33M) containing
auxiliary acid adamantane (SPI-Adaman, 0.Immol, 23mg) and ethanol (1mL) were dosed
in a 2mL reaction flask, and then I-EE-TfAc-2-Larotrectinib (0.096mmol, 84.53mg) was
dosed quickly; the reaction mixture was stirred vigorously for 4 hour at room temperature,
and TLC tracked the reaction until the raw material was completely converted; the
reaction mixture was diluted with 3mL of water, and extracted three times with
dichloromethane, 5ml each time; the organic extract phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with n-heptane/ethyl acetate=10/1, thus obtaining the labeled precursor I(III)-SPIAd-EE-2-Larotrectinib as a white solid (40.60mg, the total yield of 43.8% in two steps).
[00329] Example 84
[00330] I(III)-SPIAd-EE-5-Larotrectinib was prepared by a method similar to the
method in Example 83, and the white solid I(III)-SPIAd-EE-5-Larotrectinib was obtained
(40mg, the total yield of 43% in two steps).
[00331] Example 85
[00332] Preparation of labeled precursor I (III)-SPIAd-Als-2-Larotrectinib
~-0 N-N O O'°
. NN N N O FCCOO- 1 N N O
KIY NHN-6 N 0 F 3CCOO 1 N6I Y HN-TI O 00
C 25H 30FIN 604S:656.52 C 29 H 30FylN 60GS:882.55 I -Als-2-Larotrectinib I - Als-TfAc-2-Larotrectinib
F F 0
F3CCOO-I 0 H 0I F3CCOO NN N
0H 0 C2sH30 FylN 6OS:882.55 H C 37H 40FIN 60SS:874.72 I -Als-TfAc-2-Larotrectinib |(lii)-SPIAd -Al-2-Larotrectinib
[00333] 0.8mL of acetone was dosed in a 2 mL reactor and I-Als-2-Larotrectinib
(91.91 mg, 0.14 mmol) and mCPBA (62.86 mg, 0.22 mmol) were then dosed in a stirring
way; the mixture was stirred vigorously at 10 °C to 15 °C for 1 hour to 2 hours, 1.68mL of
SPIAd (34.5mg, 0.15mmol) dissolved in 10% sodium carbonate solution was dosed in the
reaction mixture, and the pH of the mixture was adjusted to 8 with 10% sodium carbonate
solution. The mixture was vigorously stirred at 10 °C to 15 °C for 2 hours and TLC
tracked the reaction until the raw material was completely converted; the reaction solution was transferred to a 5mL reaction flask and diluted, and then extracted three times with dichloromethane, 5 mL each time; the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure; and the residue was subjected to silica gel column chromatography
(eluted with 0-40% ethyl acetate-petroleum ether solution), thus obtaining the labeled
precursor I (III)-SPIAd-Als-2-Larotrectinib as a yellow solid (25.72mg, 21%).
[00334] Example 86
[00335] I(III)-SPIAd-Als-5-Larotrectinib was prepared by a method similar to the
method in Example 85, and the white solid I(III)-SPIAd-Als-5-Larotrectinib was obtained
(26mg, 21%).
[00336] Example 87
[00337] Preparation of labeled precursor I(III)-SPIAd-PMP-2-Larotrectinib or
F OMe F
0 ____ 0_ o\I 51NN F 3 CCOO-.
N HN_, N: N F 3CCOO KYNW N
O 0 C 28H 28FIN 60 3:642.47 C 32 H2 sF7 IN 60 7 :868.50 I - PMP-2-Larotrectinib I - PMP-TfAc-2-Larotrectinib
O OMe N-N O OMe F 3CCO0 N H NI 3 CCOO N N6 H Nrc$, NHN- ___ HI ,N
C32H 2UF7 1N 60 7 :868.50 H C 41H 42FIN 60 7:876.72 I - PMP-TfAc-2-Larotrectinib I(III)-SPIAd -PMP-2-Larotrectinib
[00338] 0.53mL of trifluoroacetic acid and 0.18mL of chloroform were dosed in a 2
mL reactor; I-PMP-2-Larotrectinib (9 6. 3 7mg 0.15 mmol), sodium chloride (0.59mg,
0.Olmmol), and Oxone (H 3 K5 0 1 8 S 4 = 614.76, 138.32mg, 0.225mmol) were dosed in a
stirring way; the mixture was heated to 80 °C and stirred to react for 3 hours, and TLC
tracked the reaction until the raw material was completely reacted; the reaction mixture was then concentrated under reduced pressure to remove the solvent; 1.2mL of ethanol and 0.68 mL of SPIAd (34.5mg, 0.15mmol) dissolved in 10% sodium carbonate solution were dosed in the residue, and the pH of the mixture was adjusted to 9 with the 10% sodium carbonate solution. The mixture was stirred at room temperature for 70 minutes;
TLC tracked the reaction till the end of the reaction; the reactant was diluted with 3mL of
water, and extracted three times with DCM, 5 mL each time; the organic phases were
combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure;
and the residue was subjected to silica gel column chromatography (eluted with 0-40%
ethyl acetate-petroleum ether solution), thus obtaining the labeled precursor I
(III)-SPIAd-PMP-2-Larotrectinib as a yellow solid (43.39mg, 33%).
[00339] Example 88
[00340] I(III)-SPIAd-PMP-5-Larotrectinib was prepared by a method similar to the
method in Example 87, and the white solid I(III)-SPIAd-PMP-5-Larotrectinib was
obtained (43mg, 33%).
[00341] Step 3: Preparation of radioisotope
[00342] Quaternary ammonium salt (TEABC) was used to replace K222 with
higher toxicity, the anion exchange cartridge was washed with acetonitrile to elute the
enriched [ 18F] fluoride, and dehydration drying was carried out for less than 5 minutes;
therefore, a short-time, low-toxicity, and high-radiochemical-purity preparation method
was provided. The preparation process of labeled product [ 18F]-Larotrectinib was as
follows:
[00343] Step (1). Preparation of [ 18F] fluoride target water: [ 18F] fluoride target
water was produced by 1 80(p,n) 18F nuclear reaction. GE PETTrace editcyclotron (which
can produce approximately 150 mCi [ 18F] fluoride target water with 40 A beam for 2
minutes) was used. [ 18F] Fluoride target water was delivered to a sterile lead-protected hot
cell of 180-enriched water by nitrogen pressure; [ 18F] fluoride target water produced by this method was usually further diluted with Milli-Q (Millipore ultrapure water instrument) ultra-purified water to obtain 1-3mCi/ml [ 18F] fluoride target water liquid before being used in research.
[00344] Step (2). Enrichment of [ 18F] fluoride by QMA anion exchange solid phase
extraction cartridge (QMA): An aliquot of the target water containing an appropriate
amount of [ 18F] fluoride was allowed to slowly pass through the anion exchange solid
phase extraction cartridge (QMA) under a nitrogen flow; the anion exchange solid phase
extraction cartridge (QMA) was pre-activated by being washing with NaHCO 3(aq)(8.4%,
1mL) and water (20 mL, until the pH indicator showed neutrality); the [ 18F] fluoride was
enriched on the QMA anion exchange solid phase extraction cartridge (QMA), and 8O
and other impurities were separated and eluted, thus obtaining [ 18F] fluorine source for the
[ 18F] fluoride QMA anion exchange solid phase extraction cartridge (QMA).
[00345] Step (3). The [ 18F] fluoride enriched on the QMA anion exchange solid
phase extraction cartridge (QMA) was eluted to obtain a quaternary ammonium salt or
inorganic salt solution of [ 18F] fluoride; the [ 18F] fluoride enriched on QMA anion
exchange solid phase extraction cartridge (QMA) was washed with a solution obtained by
dissolving an organic or inorganic base (for example, a certain amount of
tetraethylammonium bicarbonate, e.g., 8mg) in acetonitrile and water (1mL, v/v 7:3) or
acetonitrile (1mL) or methanol (1mL) or ethanol (1mL), and the [ 18F] fluoride was eluted
into a V-shaped flask sealed with a Teflon-lined diaphragm, thus obtaining an acetonitrile
aqueous solution or an acetonitrile or methanol solution of the organic or inorganic salt of
[ 18F] fluoride.
[00346] Step (4). Preparation of dry quaternary ammonium salt or inorganic salt of
[ 18F] fluoride: the V-shaped flask containing the acetonitrile aqueous solution or
acetonitrile or methanol or ethanol solution of the organic or inorganic salt of [ 18F] fluoride and sealed with a Teflon-lined diaphragm was heated to 95 °C to 110 °C, and at the same time nitrogen gas was dried by passing through the P 20 5 -DrieriteTM column and then used to blow the V-shaped flask, and then the exhaust gas was discharged through the vented flask. When no liquid was seen in the flask, the flask was taken out of the hot bath, anhydrous acetonitrile (1 mL) was then dosed in the flask, and the flask was heated again until the flask was dry. This step was repeated another three times. Then the flask was cooled at room temperature under nitrogen flow, thus obtaining dry organic or inorganic salt of [ 18F] fluoride, such as [18F]KF/K 2 CO 3/K2.2.2, [ 8F]KF/K 2 C 2 0 4 /K2 .2 .2 , [1 8F]KF/KOTf,
[ 18F]Et4NF, [ 18F]Et 4NHCO 3, [ 18F]Et 4NOMs, and [ 18F]Et4NOTf; its radioactive [ 18F]
fluoride recovery rate varied depending on the elution process used.
[00347] Step (5). Construction of labeled product [ 18F]-Larotrectinib reaction
system: the required solvent (e.g., DMF) was dosed in the V-shaped flask containing the
dry organic or inorganic salt of [ 18F] fluoride (activity meter measured (t)activity) to
re-dissolve the dry organic or inorganic salt, and the labeled precursor was then dosed to
take reaction under a certain condition, thus obtaining a crude reaction solution of
undeprotected labeled product [ 18F]-Larotrectinib.
[00348] Step (6). Deprotection of undeprotected labeled product 1[ 8F]-Larotrectinib:
a certain amount of organic base or inorganic base or organic acid or inorganic acid was or
was not dosed in the reaction solution, and the hydroxyl protecting group was removed by
heating, thus obtaining the crude reaction solution of labeled product [ 18F]-Larotrectinib.
[00349] Step (7). Separation and purification of labeled product [ 18F]-Larotrectinib:
semi-preparative HPLC or Waters Sep-Pak C-18 cartridge purification was carried out to
prepare high-purity labeled product [ 18F]-Larotrectinib, and the labeled product
[ 18F]-Larotrectinib was rinsed with a solvent into a sterile vacuum flask, blow dried with
nitrogen at 60 °C for 20 minutes, and reconstituted with brine; the obtain solution which
included 100ul of 25% Vitamin C aqueous solution and 100ul of 20% Tween 80 ethanol solution was labeled product [ 18F]-2-Larotrectinib injection.
[00350] Step (8). Analysis and identification of labeled product [ 18F]-Larotrectinib:
the identity and purity (radiochemical purity and chemical purity) of the product were
determined by radio-HPLC (60:40 CH 3 CN:H 20+0.IN ammonium formate, Phenomenex
Luna Ci8, 250 x 4.6 mm, 5 m, UV at 254 nm; CH3 CN/0.1 M NH4•HCO2(aq) (v/v, 7/3),
flow rate: 1.0 mL/min) and radio-TLC (EtOAc + 0-5% EtOH). The product had the
radiochemical purity and chemical purity of greater than 90% to 99%. The radiochemical
yield was determined as the percentage of radioactivity of the labeled precursor dosed to
the DMF-diluted [ 18F]Et 4 NHCO3 and separated as the final product from the amount of
activity in the V-shaped reaction flask, without attenuation correction. The radiochemical
yield was 20 to 45.3 (without attenuation correction), the radiochemical purity was greater
than 99%, and the specific activity was 2.56 Ci/[tmol to 18 Ci/[tmol.
[00351] The following specific examples are described for detailed explaination:
[00352] Example 89. Preparation process of organic salt or inorganic salt of 1[ 8F]
fluoride
[00353] An aliquot of the target water containing an appropriate amount of [ 18F]
fluoride was allowed to slowly pass through the anion exchange solid phase extraction
cartridge (QMA) under a nitrogen flow; the anion exchange solid phase extraction
cartridge (QMA) was pre-activated by being washed with NaHCO 3(aq)(8.4%, 1mL) and
water (20 mL, until the pH reached neutrality); the [ 18F] fluoride was enriched on the
QMA anion exchange solid phase extraction cartridge (QMA), and 18O and other
impurities were separated and eluted, thus obtaining [ 18F] fluorine source for the [ 18F]
fluoride QMA anion exchange solid phase extraction cartridge (QMA).
[00354] The [ 18F] fluoride enriched on QMA anion exchange solid phase extraction
cartridge (QMA) was washed with a solution obtained by dissolving different organic or inorganic bases in acetonitrile and water (1mL, v/v 7:3) or acetonitrile (1mL) or methanol
(1mL) or ethanol (1mL), and the [ 18F] fluoride was eluted into a V-shaped flask sealed
with a Teflon-lined diaphragm, thus obtaining an acetonitrile aqueous solution or an
acetonitrile or methanol solution of the organic or inorganic salt of [ 18F] fluoride.
[00355] The V-shaped flask containing the acetonitrile aqueous solution or
acetonitrile or methanol or ethanol solution of the organic or inorganic salt of [ 18F]
fluoride and sealed with a Teflon-lined diaphragm was heated to 95 °C to 110 °C, and at
the same time nitrogen gas was dried by passing through the P 20 5 -DrieriteTM column and
then used to blow the V-shaped flask, and then the exhaust gas was discharged through the
vented flask. When no liquid was seen in the flask, the flask was taken out of the hot bath,
anhydrous acetonitrile (1 mL) was then dosed in the flask, and the flask was heated again
until the flask was dry. This step was repeated another three times. Then the flask was
cooled at room temperature under nitrogen flow, thus obtaining dry organic or inorganic
salt of [ 18F] fluoride, such as1 [ 8F]KF/K2 C 3/K 2.2.2, [ 8F]KF/K 2 C 2 0 4 /K2 .2 .2 , [1 8F]KF/KOTf,
[ 18F]Et4NF, [ 18F]Et 4NHCO 3, [ 18F]Et 4NOMs, and [ 18F]Et4NOTf; its radioactive [ 18F]
fluoride recovery rate varied depending on the elution process used. Test data were shown
in Table 1 (Influence of different eluents and organic bases or inorganic bases on the
elution efficiency of [ 18F] fluoride) and Table 2 (Influence of different loading of organic
or inorganic bases on the elution efficiency of [ 18F] fluoride, with acetonitrile as the
elution solvent).
[00356] Table 1. Influence of different eluents and organic bases (8mg) or inorganic
bases (8mg) on the elution efficiency of [ 18F] fluoride
18F recovery K 2 C0 3/ K2 C 2 04 KOTf TEAOTf( TBAOMs( Et4NHCO 3 ( Et 4NF(T
rate (%) K 222 /K222 Et 4NOTf) Et4NOMs) TEABC) BAF)
Methanol 8.2 10.2 11.3 34.2 34.4 34.6 32.1
(1mL)
Ethanol 4.8 12.4 12.4 35.2 35.2 33.6 30.1
(1mL)
Acetonitrile 4.0 14.6 13.2 43.6 42.3 43.5 41.7
(1mL)
Acetonitrile 44.0 43.1 43.6 41.5 40.4 40.5 40.1
-water
(1mL)
Water 36.0 35.1 35.4 40.7 39.6 38.6 36.7 (1mL)
[00357] Table 2 Influence of organic or inorganic bases in different doses on the
elution efficiency of ['F] fluoride, with 1mL of acetonitrile as the elution solvent).
18 F recovery K 2 C0 3/ K2 C 2 04 KOTf TEAOTf( TBAOMs( Et4NHCO 3 ( Et 4NF(T
rate (%) K2 2 2 /K2 2 2 Et 4NOTf) Et4NOMs) TEABC) BAF)
1 mg 1.3 2.1 1.3 14.2 14.4 16.6 12.1
4 mg 4.0 14.6 13.2 43.6 42.3 43.5 41.7
8 mg 6.8 16.6 13.5 45.1 48.3 46.5 42.7
mg 8.0 16.8 13.4 44.7 47.5 45.5 42.1
12 mg 8.5 16.1 13.1 43.1 45.9 43.6 41.3
[00358] Example 90
[00359] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Bz-2-Larotrectinib.
N N N N N6 HO "H 0 O H C41 H42FIN 607 :876.72 C 2SH 26F'FN 60 3:531.55 18 1(11)-SPAd - Bz-2-Larotrectinib F -Bz-2-Larotrectinib F F
0 OOCCH5 F NN OH F N ,N 18 1F F
18 N i N F N w N
8 C2sH 26FisFN 603 : 531.55 C 21H 2 2F' FN 602: 427.45 18 - - .I.I - I-- 18 '1
[00360] Solution 1. According to the preparation process of labeled product
[ 18F]-Larotrectinib, [ 18F] fluorine source (0.5mL, activity meter measured (t)activity:
1.5mCi) QAM[ 8F] fluoride was taken and then the fluorine source QAM[18F] fluoride
anion exchange solid phase extraction cartridge (QMA) was eluted into a V-shaped
reaction flask with the solution of N,N,N,N-tetraethylammonium methanesulfonate
(TBAOMs, 8.0mg) dissolved in 1mL of acetonitrile; the obtained acetonitrile solution of
[ 18F]Et4NOMs was dehydrated to dryness by repeated azeotropic evaporation through
anhydrous acetonitrile, and the residue was diluted with anhydrous DMF (0.4mL) to
obtain a 20mg/mL [ 18F]Et 4NOMs solution.
[00361] 400uL of sample was separated from the above DMF solution and dosed in
a V-shaped reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib (4.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 120 °C and reacted for 20 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-Bz2-Larotrectinib.
[00362] Anhydrous K2C03(0.86mg) was dosed in the reaction mixture; the mixture
was then heated to 100 °C to react for 10 minutes; the reaction solution was cooled in a 0
°C ice bath; 10% HCl aqueous solution (15 L, 1.05 g/cm 3) was dropwise dosed until the
solution was neutralized to neutral. The reactant was further diluted with HPLC buffer
(60:40 CH 3CN:H 2 0+0.iN ammonium formate, 2mL), and passed through the Waters
C-18 Sep-Pak that had been washed sequentially with ethanol (1mL) and water (5mL).
Sep-Pak was rinsed with water (2mL), the desired product was eluted with ethanol (1mL), rinsed into a sterile vacuum flask, blow dried with nitrogen at 60 °C for 20 minutes, and reconstituted with brine; the obtain solution which included 100ul of 25% Vitamin C aqueous solution and 100ul 20% Tween 80 ethanol solution was labeled product
[1 8F]-Larotrectinib injection.
[00363] The sample was analyzed by radio-TLC (silica gel plate, 100% ethyl
acetate as developing agent) to determine the radiochemical conversion (RCC), and the
identity and purity of the product were determined by radioactive HPLC (60:40
CH3 CN:H20+0.1N ammonium formate, Phenomenex Luna C-18 column) and radio-TLC
(silica gel plate, 100% ethyl acetate as developing agent). The product had the
radiochemical purity of greater than 93% and the chemical purity of greater than 95%. The
co-injection method of radioactive and non-radioactive controls was carried out, and the
double detectors of radioactive detector and non-radioactive ultraviolet detector
determined the consistency of peak position to identify the labeled product. The
radiochemical yield was determined as the percentage of radioactivity of the iodonium
precursor dosed to the DMF-diluted [ 18F]Et 4NOMs solution and separated as the final
product from the amount of activity in the V-shaped reaction flask, without attenuation
correction. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 28.56%
relative to that in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is
usually 1.35mCi), and the specific activity (18.2lCi/ mol) was obtained from the final
preparation). The deprotection rate of the product was 95%.
[00364] Solution 2. The operation process here was the same as that in Solution 1
except that DMF solution was used to separate 400uL of samples respectively containing
[18F]KF/K 2 C0 3 /K 2 .2 .2 , [ 18F]KF/K 2 C 2 0 4/K 2 .2 .2 , [' 8F]KF/KOTf, [' 8F]Et 4NF, [' 8F]Et 4NHCO 3 ,
[ 18F]Et4NOMs, and [ 18F]Et 4NOTf(their radioactivities were all 1.35mCi), and the samples
were respectively dosed in V-shaped reaction flasks with the white solid labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib (4.0mg). The mixture was heated to 120 °C and reacted for 20 minutes under an airtight condition until TLC tracked that the labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared; radio-TLC tracked reaction
mixture sampling (1-2uL) and it was detected that there was the labeled product
[ 18F]-Bz-2-Larotrectinib. The subsequent steps were the same as those in Solution 1, and
the obtained product had the radiochemical purity and chemical purity of greater than 99%.
The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi) and the
specific activity were shown in Table 3 below.
[00365] Table 3. Influence of organic or inorganic base in different doses on the
radiochemical yield and specific activity of [ 18F]-2-Larotrectinib
K 2 C0 3/ K2 C 2 04 KOTf TEAOTf( TBAOMs( Et4NHC Et 4NF
K222 /K222 Et 4NOTf) Et4NOMs) 03 (TBAF) (TE ABC)
RCC(%) 0.08 8.62 0.56 25.0 28.0 26.4 22.1
Specific
activity 0.001 0.1 0.002 12.8 18.0 14.1 11.5 (Ci/pm
ol)
[00366] Solution 3. The operation process here was the same as that in Solution 1
except that the fluorine source QAM[ 18F] fluoride anion exchange solid phase extraction
cartridge (QMA) was eluted into a V-shaped reaction flask with the solution of
N,N,N,N-tetraethylammonium methanesulfonate (TBAOMs, 8mg) dissolved in 1mL of
acetonitrile; the obtained acetonitrile solution of [ 18F]Et4NOMs was dehydrated to dryness
by repeated azeotropic evaporation through anhydrous acetonitrile, and the residue was
diluted with different anhydrous solvents DMF (0.4mL), DMSO (0.4mL), DMA (0.4mL),
CH3CN (0.4mL), and NMP (0.4mL) to obtain 10mg/mL [ 18F]Et4NOMs solution. The subsequent steps were the same as those in Solution 1, and the obtained product had the radiochemical purity and chemical purity of greater than 99%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib relative to that in the V-shaped reaction flask
(the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi) and the specific activity were
shown in Table 4 below.
[00367] Table 4. Influence of different solvents on the radiochemical yield and
specific activity of [ 18F]-2-Larotrectinib
DMSO DMA CH 3 CN NMP DMF(0.4 mL) (0.4 mL) (0.4 mL) (0.4 mL) (0.4 mL)
RCC(%) 28.0 27.2 26.1 27.8 21.0
Specific
activity 18.0 16.9 15.6 17.2 10.5 (Ci/ mol)
[00368] Solution 4. The operation process was the same as that in Solution 1 except
that the fluorine source QAM[ 18F] fluoride anion exchange solid phase extraction
cartridge (QMA) was respectively eluted into a V-shaped reaction flask with the solutions
of N,N,N,N-tetraethylammonium methanesulfonate in different doses (TBAOMs, 1mg,
4.0mg, 8mg, 10mg, 12mg) dissolved in 1mL of acetonitrile; the obtained acetonitrile
solution of [ 18F]Et 4NOMs was dehydrated to dryness by repeated azeotropic evaporation
through anhydrous acetonitrile, and the residue was diluted with anhydrous DMF (0.4mL)
to obtain 10mg/mL [ 18F]Et 4NOMs solution. The subsequent steps were the same as those
in Solution 1, and the obtained product had the radiochemical purity and chemical purity
of greater than 99%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib relative
to that in the V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually
1.35mCi) and the specific activity were shown in Table 5 below.
[00369] Table 5. Influence of organic or inorganic base in differnt doses on the
radiochemical yield and specific activity of [ 18F]-2-Larotrectinib
TBAOMs TBAOMs(E TBAOMs(Et 4 TBAOMs(Et 4 TBAOMs(Et 4 (Et 4NOMs) t4NOMs) 8 NOMs) NOMs) NOMs) 4 mg 1 mg mg 10 mg 12 mg
RCC(%) 0.08 8.62 28.0 25.0 28.0
Specific
activity 0.001 0.1 18.0 12.8 18.0
(Ci/pmol)
[00370] Solution 5. The operation process here was the same as that in Solution 1
except that 400uL of sample was separated from the above DMF solution and dosed in a
V-shaped reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib (4.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to different temperatures, e.g., 100 °C, 110 °C, 120 °C,
135 °C, 145 °C, 155 °C, and 160 °C and reacted for 20 minutes respectively under an
airtight condition until TLC tracked that the labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared. The subsequent steps were the
same as those in Solution 1, and the obtained product had the radiochemical purity and
chemical purity of greater than 99%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib relative to that in the V-shaped reaction flask (the radioactivity of
[ 18F] Et 4NOMs is usually 1.35mCi) and the specific activity were shown in Table 6 below.
[00371] Table 6. Influence of different reaction temperatures on the radiochemical
yield and specific activity of [ 18F]-2-Larotrectinib
100°C 110°C 120°C 135°C 145°C 155°C 160°C
RCC(%) 24.2 26.1 28.0 28.0 28.0 28.0 28.0
Specific
activity 14.3 15.6 18.0 18.0 18.0 18.0 18.0
(Ci/ mol)
[00372] Solution 6. The operation process here was the same as that in Solution 1 except that 400uL of sample was separated from the above DMF solution and dosed in
V-shaped reaction flasks containing the white solid labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib in different doses (0.5mg, 1.0mg, 2.0mg, 4.0mg, 6mg)
(the radioactivity of [ 18F]Et 4NOMs is usually 1.35 mCi). The mixture was heated to 145
°C and reacted for 20 minutes under an airtight condition until TLC tracked that the
labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared. The subsequent
steps were the same as those in Solution 1, and the obtained product had the radiochemical
purity and chemical purity of greater than 99%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib relative to that in the V-shaped reaction flask (the radioactivity of
[ 18F] Et 4NOMs is usually 1.35mCi) and the specific activity were shown in Table 7 below.
[00373] Table 7. Influence of labeled precursor in different doses on the
radiochemical yield and specific activity of [ 18F]-2-Larotrectinib
Labeled Labeled Labeled Labeled Labeled
precursor precursor precursor precursor precursor
0.5mg 1.0 mg 2.0 mg 4.0 mg 6.0 mg
RCC(%) 26.8 28.1 28.2 28.2 28.3
Specific
activity 16.1 18.0 18.1 17.6 17.4
(Ci/ mol)
[00374] Solution 7. The operation process here was the same as that in Solution 1
except that 400uL of sample was separated from the above DMF solution and dosed in a
V-shaped reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib (0.5 mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was respectively heated to 120 °C, 135 °C, 145 °C, 155 °C, and
160 °C and reacted for different times, e.g., 5 minutes, 10 minutes, 15 minutes, and 20
minutes under an airtight condition until TLC tracked that the labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared. The subsequent steps were the
same as those in Solution 1, and the obtained product had the radiochemical purity and
chemical purity of greater than 99%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib relative to that in the V-shaped reaction flask (the radioactivity of
[ 18F] Et 4NOMs is usually 1.35mCi) and the specific activity were shown in Table 8 below.
[00375] Table 8. Influence of different labeling reaction times on the radiochemical
yield and specific activity of [ 18F]-2-Larotrectinib
Temperature Specific activity Time (min) RCC(%) (C) (Ci/ mol)
12 15.3 7.6
15 17.9 10.2 120 °C 18 23.4 14.2
20 28.0 18.0
12 18.4 9.7
15 23.8 14.5 135 °C 18 28.0 18.0
20 28.0 18.0
8 17.6 9.3
12 23.7 14.6
145 °C 15 28.0 18.0
18 28.0 18.0
20 27.8 15.6
8 18.3 9.8
10 24.6 13.8
155 °C 12 28.0 18.0
15 28.0 17.1
18 27.5 16.6
160 °C 5 13.5 6.7
8 16.8 8.9
12 27.6 15.4
15 27.7 14.9
18 26.3 14.3
[00376] Solution 8. According to the preparation process of labeled product
[ 18F]-Larotrectinib, [ 18F] fluorine source (0.5mL, activity meter measured (t)activity:
1.5mCi) QAM[ 8F] fluoride was taken and then the fluorine source QAM[18F] fluoride
anion exchange solid phase extraction cartridge (QMA) was eluted into a V-shaped
reaction flask with the solution of N,N,N,N-tetraethylammonium methanesulfonate
(TBAOMs, 8.0mg) dissolved in 1mL of acetonitrile; the obtained acetonitrile solution of
[ 18F]Et4NOMs was dehydrated to dryness by repeated azeotropic evaporation through
anhydrous acetonitrile, and the residue was diluted with anhydrous DMF (0.4mL) to
obtain a 20mg/mL [ 18F]Et 4NOMs solution.
[00377] 400uL of sample was separated from the above DMF solution and dosed in
a V-shaped reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-Bz-2-Larotrectinib.
[00378] Anhydrous potassium tert-butoxide (KOtBu, 0.70mg) was dosed in the
reaction mixture; the mixture was then heated to 80 °C to react for 8 minutes; the reaction
solution was cooled in a 0 °C ice bath; 10% HCl aqueous solution (15 L, 1.05 g/cm3) was
dropwise dosed until the solution was neutralized to neutral. The reactant was further
diluted with HPLC buffer (60:40 CH3CN:H20+0.1N ammonium formate, 2mL), and
passed through the Waters C-18 Sep-Pak that had been washed sequentially with ethanol
(1mL) and water (5mL). Sep-Pak was rinsed with water (2mL), the desired product was
eluted with ethanol (1mL), rinsed into a sterile vacuum flask, blow dried with nitrogen at
°C for 20 minutes, and reconstituted with brine; the obtain solution which included
100ul of 25% Vitamin C aqueous solution and 100ul 20% Tween 80 ethanol solution was
labeled product [1 8F]-2-Larotrectinib injection.
[00379] The sample was analyzed by radio-TLC (silica gel plate, 100% ethyl
acetate as developing agent) to determine the radiochemical conversion (RCC), and the
identity and purity of the product were determined by radioactive HPLC (60:40
CH3 CN:H20+0.1N ammonium formate, Phenomenex Luna C-18 column) and radio-TLC
(silica gel plate, 100% ethyl acetate as developing agent). The product had the
deprotection rate of 100% and the radiochemical purity and chemical purity of greater
than 99%. The co-injection method of radioactive and non-radioactive controls was
carried out, and the double detectors of radioactive detector and non-radioactive ultraviolet
detector determined the consistency of peak position to identify the labeled product. The
radiochemical yield was determined as the percentage of radioactivity of the iodonium
precursor dosed to the DMF-diluted [ 18F]Et 4NOMs solution and separated as the final
product from the amount of activity in the V-shaped reaction flask, without attenuation
correction. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 41.82%
relative to that in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is
usually 1.35mCi), and the specific activity (27.11Ci/ mol) was obtained from the final
preparation).
[00380] Example 91
[00381] Similar to the method of Example 90, the labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Bz-5-Larotrectinib, the product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 41.15% relative to that in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity (27.13Ci/ mol) was obtained from the final preparation).
[00382] Example 92
[00383] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-TBS-2-Larotrectinib.
O~N H~ HN
18 H C40H 50 FIN 6O6Si:884.86 C 27 H36 F FN 60 2 Si:541.71 |(Ill)-SPIAd -TBS - 2-Larotrectinib IsF -TBS-2- Larotrectinib
18F Ni N F N N6
0 0 8 C2 1 H 22 F'FN6 0 2 :427.45 C 27H 36F' FN6 02 Si:541.71 18 F -TBS-2- Larotrectinib 'OF - 2-Larotrectinib
[00384] According to the preparation process of labeled product [ 18F]-Larotrectinib,
[ 18F] fluorine source (0.5mL, activity meter measured (t)activity: 1.5mCi) QAM[ 8F]
fluoride was taken and then the fluorine source QAM[ 18F] fluoride anion exchange solid
phase extraction cartridge (QMA) was eluted into a V-shaped reaction flask with the
solution of N,N,N,N-tetraethylammonium methanesulfonate (TBAOMs, 8.0mg) dissolved
in 1mL of acetonitrile; the obtained acetonitrile solution of [ 18F]Et 4NOMs was dehydrated
to dryness by repeated azeotropic evaporation through anhydrous acetonitrile, and the
residue was diluted with anhydrous DMF (0.4mL) to obtain a 20mg/mL [ 18F]Et 4NOMs
solution.
[00385] 400uL of sample was separated from the above DMF solution and dosed in a V-shaped reaction flask containing the white solid labeled precursor
I(III)-SPIAd-TBS-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-TBS-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-2-Larotrectinib.
[00386] The reactant was further diluted with HPLC buffer (60:40
CH3 CN:H20+0.1N ammonium formate, 2mL), and passed through the Waters C-18
Sep-Pak that had been washed sequentially with ethanol (1mL) and water (5mL). Sep-Pak
was rinsed with water (2mL), the desired product was eluted with ethanol (1mL), rinsed
into a sterile vacuum flask, blow dried with nitrogen at 60 °C for 20 minutes, and
reconstituted with brine; the obtain solution which included 100ul of 25% Vitamin C
aqueous solution and 100ul of 20% Tween 80 ethanol solution was labeled product
[1 8F]-2-Larotrectinib injection.
[00387] The sample was analyzed by radio-TLC (silica gel plate, 100% ethyl
acetate as developing agent) to determine the radiochemical conversion (RCC), and the
identity and purity of the product were determined by radio-HPLC (60:40
CH3 CN:H20+0.1N ammonium formate, Phenomenex Luna C-18 column) and radio-TLC
(silica gel plate, 100% ethyl acetate as developing agent). The product had the
radiochemical purity and chemical purity of greater than 99%. The co-injection method of
radioactive and non-radioactive controls was carried out, and the double detectors of
radioactive detector and non-radioactive ultraviolet detector determined the consistency of
peak position to identify the labeled product. The radiochemical yield was determined as
the percentage of radioactivity of the iodonium precursor dosed to the DMF-diluted
[ 18F]Et4NOMs solution and separated as the final product from the amount of activity in
the V-shaped reaction flask, without attenuation correction. The uncorrected radiochemical yield of [1 8F]-2-Larotrectinib was 45.82% relative to that in the V-shaped reaction flask
(the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity
(29.82Ci/ mol) was obtained from the final preparation).
[00388] Example 93
[00389] Similar to the method of Example 92, labeled product [ 18F]-5-Larotrectinib
was prepared from the labeled precursor I(III)-SPIAd-TBS-5-Larotrectinib. The product
had the deprotection rate of 100% and the radiochemical purity and chemical purity of
greater than 99%. The uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was
45.21% relative to that in the V-shaped reaction flask (the radioactivity of [ 8 F] Et4NOMs
is usually 1.35mCi), and the specific activity (29.81Ci/ mol) was obtained from the final
preparation).
[00390] Example 94
[00391] Labeled product [ 18F]2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-SEM-2-Larotrectinib.
H C 4 0 H5 0FIN 607 Si:900.86 C27 H36 FisFN 60 3 Si:557.71 18 1(ll)-SPIAd -SEM-2-Larotrectinib F -SEM- 2-Larotrectinib F F 0 oY 18 NN OSEM 1 NIYN OH F NN F N N
C 27 HFF0FN6 07 Si:557.71 C 21H22F 6FN 60 2: 427.450 18 18 F -SEM- 2-Larotrectinib F -2- Larotrectinib
[00392] The operation in this example was the same as that in Example 91. The
product has the deprotection rate of100% or above and the radiochemical purity and
chemical purity of greater than 9900. The uncorrected radiochemical yield of
[ 18 F]-2-Larotrectinib was45.82 relative tothat in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity
(29.82Ci/ mol) was obtained from the final preparation).
[00393] Example 95
[00394] Similar to the method of Example 94, labeled product [ 18F]-5-Larotrectinib
was prepared from the labeled precursor I(III)-SPIAd-SEM-5-Larotrectinib. The product
had the deprotection rate of 100% and the radiochemical purity and chemical purity of
greater than 99%. The uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was
45.55% relative to that in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs
is usually 1.35mCi), and the specific activity (29.80Ci/ mol) was obtained from the final
preparation).
[00395] The product was re-sampled and detected by radio-TLC until deprotection
was completed. The reaction mixture was neutralized with 5N sodium hydroxide (5N,
0.2mL) and diluted with HPLC mobile phase (10% ethanol, 28mM hydrochloric acid,
nM ammonium acetate, pH2, 0.5mL). The diluted solution was injected into a
semi-preparative HPLC (static phase: Hamilton PRP-1, 250x 10 mm, 10 um; mobile phase
same as above, 3.5mL/min, tR = -17min), the eluent containing the product was collected
step by step; the activity was detected by an activity meter, the separation rate of 80%
(without attenuation correction) was also calculated, and the total time (from to to the end
of the synthesis EOS) 75 2 minutes. The product has the radiochemical purity and
chemical purity of 95% to 99% and the deprotection conversion rate of 98% or above.
[00396] The mixture (2uL) was subjected to TLC thin-plate chromatography
(developing agent: 100% ethyl acetate) to determine the labeling rate (RCC), then diluted
with 15 mL of water, passed through a solid phase extraction cartridge with C18 filler,
eluted with water (24 mL), and rinsed with acetonitrile (1.5 mL), and the resulting mixture
was collected in a micropycnometer.
[00397] The mixture (20uL) and fluorine-19 standard control ( 19F-Larocetrinib) were co-injected into radio-HPLC to determine the 18F-labeled product ( 18F-Larocetrinib).
The residual reaction mixture was neutralized with 5N sodium hydroxide (5N, 0.2mL) and
diluted with HPLC mobile phase (10% ethanol, 28mM hydrochloric acid, 20nM
ammonium acetate, pH2, 0.5mL). The diluted solution was injected into a
semi-preparative HPLC (static phase: Hamilton PRP-1, 250x 10 mm, 10 um; mobile phase
same as above, 3.5mL/min, tR = -17min), the eluent containing the product was collected
step by step; the activity was detected by an activity meter, the separation rate of 80%
(without attenuation correction) was also calculated, and the total time (from to to the end
of the synthesis EOS) 75 2 minutes. The product has the radiochemical purity and
chemical purity of 95% to 99% and the deprotection conversion rate of 98% or above.
[00398] Example 96
[00399] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-TBDPS-2-Larotrectinib.
0 N.-N OTBDPS /-N OTBDPS H O O N-. H-_ N N6
19 H C5 0H 54FIN 60 6SI: 1009.01 Ca 7H 4,F FIN 6O 2Si:666.85 I(III)-SPIAd -TBDPS -2- Larotrectinib 19 F -TBDPS-2-Larotrectinib
19 -N OTBDPS -N OH F N N 19F NN
C3 yH 4 F'9FIN 6O 2Si:666.85 C 21H 22FFINS02 :428.44 1 19 9F -TBDPS-2-Larotrectinib F -2- Larotrectinib
[00400] The operation in this example was the same as that in Example 92. The
deprotection conversion rate was 100% or above. The product had the radiochemical
purity and chemical purity of greater than 99%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib was 45.80% relative to that in the V-shaped reaction flask (the
radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity
(29.84Ci/ mol) was obtained from the final preparation).
[00401] Example 97
[00402] Similar to the method of Example 96, labeled product [ 18F]-5-Larotrectinib
was prepared from the labeled precursor I(III)-SPIAd-TBDPS-5-Larotrectinib. The
product had the deprotection rate of 100% and the radiochemical purity and chemical
purity of greater than 99%. The uncorrected radiochemical yield of [ 18F]-5-Larotrectinib
was 45.50% relative to that in the V-shaped reaction flask (the radioactivity of [ 18F]
Et4NOMs is usually 1.35mCi), and the specific activity (29.83Ci/ mol) was obtained
from the final preparation).
[00403] Example 98
[00404] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-TIPS-2-Larotrectinib.
0 N'N
N HNF OTIPS 19F /N
19 H C 4 3H 56FIN 60 6Si: 926.94 C 3yH2F FIN 6O2Si:584.79 |(Ill)-SPIAd -TIPS - 2-Larotrectinib 19 F -TIPS-2-Larotrectinib
19F N1N9F N
0 0 C 37H 42F'9FIN 6 02Si:584.79 C21 H22F"FIN 60 2:428.44 19 F -TIPS-2-Larotrectinib '9F - 2-Larotrectinib
[00405] The operation in this example was the same as that in Example 92. the
deprotection conversion rate of 100% or above. The product had the radiochemical purity and chemical purity of greater than 99%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib was 45.89% relative to that in the V-shaped reaction flask (the
radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity
(29.82Ci/ mol) was obtained from the final preparation).
[00406] Example 99
[00407] Similar to the method of Example 98, labeled product [ 18F]-5-Larotrectinib
was prepared from the labeled precursor I(III)-SPIAd-TIPS-5-Larotrectinib. The product
had the deprotection rate of 100% and the radiochemical purity and chemical purity of
greater than 99%. The uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was
45.23% relative to that in the V-shaped reaction flask (the radioactivity of 1[8 F] Et4NOMs
is usually 1.35mCi), and the specific activity (29.3lCi/ mol) was obtained from the final
preparation).
[00408] Example 100
[00409] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Teoc-2-Larotrectinib.
F F 0 0
1N-N0
H ON N1F N Nr§ 'H O O 1 H C 40H48F1N 609 Si:914.85 FN 60 4 Si:571.69 C27 H 34 F 18 |(III)-SPAd -Teoc-2-Larotrectinib F -Teoc- 2-Larotrectinib
0 F FH
18NN Ho
[00410] The operation in this example was the same as that in Example 92. The
product had the deprotection conversion rate of 100% or above and the radiochemical
purity and chemical purity of greater than 99%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib was 45.82% relative to that in the V-shaped reaction flask (the
radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity
(29.80Ci/Umol) was obtained from the final preparation).
[00411] Example 101
[00412] Similar to the method of Example 100, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-TPIS-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.27% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific
activity (29.31Ci/umol) was obtained from the final preparation).
[00413] Example 102
[00414] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursor I(III)-SPIAd-Piv-2-Larotrectinib.
F F 0 0
F N N HH N - N 18F$ S
H, O QHN QJ, N HN6L
18 H C3 H"FIN6O 7: 854.72 C26H 30F FIN 603:511.56 I(lll)-SPIAd -Piv-2- Larotrectinib I - Pv-2-Larotrectinib
F F 0
NF N 18 F N N OH 18 F F
18 18 C 26HaoF FIN 6O0:511.56 C21 H22F FIN 602:427.45 I -Piv-2-Larotrectinib 'OF -2- Larotrectinib
[00415] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 1 8F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Piv-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Piv-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-Piv-2-Larotrectinib.
[00416] Sodium methoxide powder (NaOMe, 0.71mg) was dosed in the reaction
mixture; the mixture was then heated to 90 °C to react for 8 minutes; the reaction solution
was cooled in a 0 °C ice bath; 10% HC aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 100% or
above and the radiochemical purity and chemical purity of greater than 99%. The
uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 45.83% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (29.85Ci/ mol) was obtained from the final preparation).
[00417] Example 103
[00418] Similar to the method of Example 102, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Piv-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.64% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the specific
activity (29.44Ci/ mol) was obtained from the final preparation).
[00419] Example 104
[00420] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Ac-2-Larotrectinib.
NN OA N'N OAC He N CH, 1\ N NH3 N F
0
H C36H 3 F1IN 607:812.64 1 8 C2 3H24 FFIN 603:469.48 1(11)-SPIAd-Ac-2-Larotrectinib 1F- Ac-2-Larotrectinib
18F, N0 N_,N Ha 1aF N F F
/ N OH 18 18 F F K Ni HN-_,NN
18 18 C 23H 2 4F FIN6 03:469.48 C 23 H24 F FIN 602 :427.45 18 '- Ac-2-Larotrectinib F- 2-Larotrectinib
[00421] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 1 8F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor I(III)-SPIAd-Ac-2-Larotrectinib
(1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually 1.35 mCi). The mixture was heated
to 155 °C and reacted for 12 minutes under an airtight condition until TLC tracked that the
labeled precursor I(III)-SPIAd-Ac-2-Larotrectinib basically disappeared; radio-TLC
tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product [1 8F]-Ac-2-Larotrectinib.
[00422] Sodium methoxide powder (NaOMe, 0.11mg) was dosed in the reaction
mixture; the mixture was then heated to 80 °C to react for 8 minutes; the reaction solution
was cooled in a 0 °C ice bath; 10% HC aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 100% or
above and the radiochemical purity and chemical purity of greater than 99%. The
uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 45.84% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (29.88Ci/ mol) was obtained from the final preparation).
[00423] Example 105
[00424] Similar to the method of Example 104, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Ac-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.54% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the specific
activity (29.25Ci/ mol) was obtained from the final preparation).
[00425] Example 106
[00426] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Tf-2-Larotrectinib.
F F 0 0
N 1aFN NCF N CF 3 H 0 0 H C36H 3sF4 |N 60 7:866.61 C23H 21F 418FIN 60 3:523.45 I(Ill)-SPIAd -Tf 2-Larotrectinib 1 F-Tf-2-Larotrectinib
18 F NN$ O; N
18 1 C 23H 21F 4 FIN 603:523.45 C2 3H24F FIN 6O2:427.45 18 18F -T-2-Larotrectinib F- 2-Larotrectinib
[00427] According to the preparation process of labeled product [18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor I(III)-SPIAd-Tf-2-Larotrectinib
(1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually 1.35 mCi). The mixture was heated
to 155 °C and reacted for 12 minutes under an airtight condition until TLC tracked that the
labeled precursor I(III)-SPIAd-Tf-Larotrectinib basically disappeared; radio-TLC tracked
reaction mixture sampling (1-2uL) and it was detected that there was the labeled product
[1 8F]-Tf-2-Larotrectinib.
[00428] Sodium ethoxide powder (NaOEt, 0.15mg) was dosed in the reaction
mixture; the mixture was then heated to 80 °C to react for 6 minutes; the reaction solution
was cooled in a 0 °C ice bath; 10% HC aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 100% or
above and the radiochemical purity and chemical purity of greater than 99%. The
uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 45.45% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (29.65Ci/ mol) was obtained from the final preparation).
[00429] Example 107
[00430] Similar to the method of Example 106, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Tf-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.78% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the specific
activity (29.54Ci/ mol) was obtained from the final preparation).
[00431] Example 108
[00432] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-CAc-2-Larotrectinib.
F F 0 0
HJ 18 / N CH2CHICI 1F N
HN~ K NHN J
H C 36H 37CIFINS0 7:847.08 1 C 23H 23 CF FIN 603:503.93 1(111-SPIAd-CAc-2-Larotrectinib 18 F-CAc-2-Larotrectinib
F F 0 /N- OA'~CHCI / N OH 18 1F F K
18 18 C23 H2 3CIF F1N 60 3:503.93 C2 3H 24 F FIN102 :427.45 8 'OF -CAc-2-Larotrectinib I F-2- Larotrectinib
[00433] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-CAc-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight condition until TLC tracked that the labeled precursor I(III)-SPIAd-CAc-2-Larotrectinib basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product [ 18F]-CAc-2-Larotrectinib.
[00434] Sodium ethoxide powder (NaOEt, 0.15mg) was dosed in the reaction
mixture; the mixture was then heated to 80 °C to react for 6 minutes; the reaction solution
was cooled in a 0 °C ice bath; 10% HC aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 100% or
above and the radiochemical purity and chemical purity of greater than 99%. The
uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 45.83% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (29.87Ci/ mol) was obtained from the final preparation).
[00435] Example 109
[00436] Similar to the method of Example 108, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-CAc-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.25% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the specific
activity (29.12Ci/ mol) was obtained from the final preparation).
[00437] Example 110
[00438] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-DCAc-2-Larotrectinib.
F F 0 0
0 N'N OA Cl2 51N'N OAC~l H I - NCHCI 181$CHCI,
H ¾ NI N 1aF N Na H__ IP 1Z-00 99 1000 ON_ 18 H C36H 36C12FING0 7:881.52 C23H 22C1 2F FIN$0 3:53$.37 iIIfla.ntPi _nra n-A .Attnh C H 2CF -I :383
* N N C OHC2 1 N OH 18 18 FK F
CT ~HN_( 1 1 C23 H2 2Cl 2F FIN 60 3:538.37 C2 aH 24F sFIN 6O2 :427.45 18 F-DCAc-2-Larotrectinib iOF-2-Larotrectinib
[00439] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-DCAc-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-DCAc-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-DCAc-2-Larotrectinib.
[00440] Sodium methoxide powder (NaOMe, 0.11mg) was dosed in the reaction
mixture; the mixture was then heated to 80 °C to react for 5 minutes; the reaction solution
was cooled in a 0 °C ice bath; 10% HC aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 100% or
above and the radiochemical purity and chemical purity of greater than 99%. The
uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 45.85% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (29.86Ci/ mol) was obtained from the final preparation).
[00441] Example 111
[00442] Similar to the method of Example 110, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-DCAc-5-Larotrectinib. The product had the deprotection rate of 100% and
the radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.53% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the specific
activity (29.24Ci/ mol) was obtained from the final preparation).
[00443] Example 112
[00444] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Moc-2-Larotrectinib.
F F 0 0
H C36HasFINGOO: 828.64 C2aH24FiOFINSO4:485.48 I(lll)-SPIAd -Moc-2- Larotrectinib 'OF - Moc-2-Larotrectinib 00
S -N O /N OH 18 F 18F N N
0 0 18 1 C 23H 24 F FIN 604:485.48 C 23H24F sFIN 6O2 :427.45 18 18 F - Moc-2-Larotrectinib F- 2-Larotrectinib
[00445] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Moc-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight condition until TLC tracked that the labeled precursor I(III)-SPIAd-Moc-2-Larotrectinib basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product [ 18F]-Moc-2-Larotrectinib.
[00446] Potassium hydroxide (KOH, 0.37mg) was dosed in the reaction mixture;
the mixture was then heated to 100 °C to react for 12 minutes; the reaction solution was
cooled in a 0 °C ice bath; 10% HCl aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 89.8% or
above, the radiochemical purity of 96.3% and the chemical purity of greater than 91.3%.
The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 35.45% relative to that
in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi),
and the specific activity (22.33Ci/ mol) was obtained from the final preparation).
[00447] Example 113
[00448] Similar to the method of Example 112, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Moc-5-Larotrectinib. The product had the deprotection rate of 89% and the
radiochemical purity of greater than 96% and chemical purity of greater than 91%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 35.56% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (22.23Ci/ mol) was obtained from the final preparation).
[00449] Example 114
[00450] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Eoc-2-Larotrectinib.
F F F~ 0 OF0 0 N'N OA NN O
H103
-N O N'- OH 18 N F N
0 0 18 1 C2 4H 26F FIN 6O 4 :499.51 C 23H 24F sFIN 602:427.45 18 18 F-Eoc-2-Larotrectinib F-2-Larotrectinib
[00451] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Eoc-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Eoc-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-Eoc-2-Larotrectinib.
[00452] Potassium hydroxide (KOH,0.37mg) was dosed in the reaction mixture; the
mixture was then heated to 100 °C to react for 12 minutes; the reaction solution was
cooled in a 0 °C ice bath; 10% HC aqueous solution was dropwise dosed until the
solution was neutralized to neutral. The subsequent operation in this example was the
same as that in Example 92. The product had the deprotection conversion rate of 90.2% or
above, the radiochemical purity of 97.5% and the chemical purity of greater than 90.1%.
The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 32.15% relative to that
in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi),
and the specific activity (21.43Ci/ mol) was obtained from the final preparation).
[00453] Example 115
[00454] Similar to the method of Example 114, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Eoc-5-Larotrectinib. The product had the deprotection rate of 90% and the
radiochemical purity of greater than 97% and chemical purity of greater than 90%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 32.35% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (21.14Ci/ mol) was obtained from the final preparation).
[00455] Example 116
[00456] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Boc-2-Larotrectinib.
F F 0 0
HH; ONN NOA 1_NN
H 0 H C39H4FIN 6OO: 870.72 18 C26H 30F FIN 60 4:527.56 I(III)-SPIAd -Boc-2- Larotrectinib 'OF - Boc-2-Larotrectinib
-N 0 O N OH
18F N1N8F 0 0 NN O OH
18 18 C 2,HaoF FIN104 :527.56 C23 H24F FINI02:427.45 18 1 F-Boc-2-Larotrectinib F-2-Larotrectinib
[00457] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Boc-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Boc-2-Larotrectinib basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product [ 18F]-Boc-2-Larotrectinib.
[00458] Trifluoroacetic acid (CF 3COOH, 0.75mg) was dosed in the reaction
mixture; the mixture was then heated to 100 °C to react for 6 minutes; the reaction
solution was cooled in a 0 °C ice bath; 10% HCl aqueous solution was dropwise dosed
until the solution was neutralized to neutral. The subsequent operation in this example was
the same as that in Example 92. The product had the deprotection conversion rate of 100%
or above, the radiochemical purity of 99% and the chemical purity of greater than 99%.
The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 42.35% relative to that
in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi),
and the specific activity (28.25Ci/ mol) was obtained from the final preparation).
[00459] Example 117
[00460] Similar to the method of Example 116, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Boc-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity and chemical purity of greater than 99%. The uncorrected
radiochemical yield of [ 18F]-5-Larotrectinib was 45.35% relative to that in the V-shaped
reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the specific
activity (29.51Ci/ mol) was obtained from the final preparation).
[00461] Example 118
[00462] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Troc-2-Larotrectinib.
O N'N O O CCl3 NO H18FO H O H N i N N CC0
Z 60
8 H C37H37CI 3FIN60S:945.99 C24H 2 C1 3F FIN 604:602.84 I(III)-SPIAd Troc-2-Larotrectinib 106 'OF -Troc-2-Larotrectinib
X 'IN O. O... OH 18F 0
N CCI3 NN'
0 0 8 1 C 24H 23CI13F FING04 :602.84 C 23 H 24 F 1 FIN 602 :427.45 18 18 F- Troc-2-Larotrectinib F- 2-Larotrectinib
[00463] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Troc-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Troc-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-Troc-2-Larotrectinib.
[00464] Acetic acid (CH 3 COOH, 0.35mg) and zinc powder (Zn, 0.82mg) were
dosed in the reaction mixture; the mixture was then heated to 100 °C to react for 8 minutes;
the reaction solution was cooled in a 0 °C ice bath; 10% HCl aqueous solution was
dropwise dosed until the solution was neutralized to neutral. The subsequent operation in
this example was the same as that in Example 92. The product had the deprotection
conversion rate of 95.8% or above, the radiochemical purity of 97.6% and the chemical
purity of greater than 95%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib
was 38.63% relative to that in the V-shaped reaction flask (the radioactivity of 1[ 8F]
Et4NOMs is usually 1.35mCi), and the specific activity (25.43Ci/ mol) was obtained from
the final preparation).
[00465] Example 119
[00466] Similar to the method of Example 118, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Troc-5-Larotrectinib. The product had the deprotection rate of 95% and the
radiochemical purity of greater than 97.5% and chemical purity of greater than 97.5%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 38.35% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (25.41Ci/ mol) was obtained from the final preparation).
[00467] Example 120
[00468] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-PMB-2-Larotrectinib.
O N'N O OMe NN O OMe 0 0
N 0 HN
H C4 2H4FIN6 O 7:890.75 C2,H 3 oFisFIN 60 3 :547.60 I(III)-SPIAd-PMB-2-Larotrectinib I(III)-SPIAd-PMB-2-Larotrmctinib
F F /\, OMe 18 N'N O O N OH 18 F F 18 N N__F N6 N6
8 18 C2 ,HaoF' FIN 6 O3:547.60 C2 3H24F FIN 6O2:427.45 1 |(Ill)-SPIAd-PMB-2-Larotrectinib sF-2-Larotrectinib
[00469] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-PMB-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-PMB-2-Larotrectinib basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product [ 18F]-PMB-2-Larotrectinib.
[00470] 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DQQ, 0.0033mmol, 0.75mg)
was dosed in the reaction mixture; the mixture was then heated to 100 °C to react for 12
minutes; the reaction solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous
solution was dropwise dosed until the solution was neutralized to neutral. The subsequent
operation in this example was the same as that in Example 92. The product had the
deprotection conversion rate of 91.7% or above, the radiochemical purity of 95.6% and
the chemical purity of greater than 90.7%. The uncorrected radiochemical yield of
[ 18F]-2-Larotrectinib was 37.43% relative to that in the V-shaped reaction flask (the
radioactivity of [ 18F] Et4NOMs is usually 1.35mCi), and the specific activity (23.12
Ci/ mol) was obtained from the final preparation).
[00471] Example 121
[00472] Similar to the method of Example 120, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-PMB-5-Larotrectinib. The product had the deprotection rate of 95% and the
radiochemical purity of greater than 97.5% and chemical purity of greater than 97.5%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 38.35% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (25.4OCi/ mol) was obtained from the final preparation).
[00473] Example 122
[00474] Labeled product [ 18F]-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-PMP-Larotrectinib.
F F O OMe N OMe
0HN 18 F\< ~ N H,5 N 1s
18 H C4 1H 42 FIN6 0 7:876.72 C 2SH2 SF FIN 6 03:533.57 I(III)-SPIAd -PMP-2-Larotrectinib |(III)-SPIAd -PMP-2-Larotrectinib
OMe
1 N N6F N N6
0 O 1 8 C2 ,H 28F' FIN 6 03 :533.57 C2 3H24F sFIN 6O2:427.45 1 I(III)-SPIAd-PMP-2-Larotrectinib F-2-Larotrectinib
[00475] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-PMP-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-PMP-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-PMP-2-Larotrectinib.
[00476] Cerium ammonium nitrate (CAN, 0.0033mmol, 1.81mg) was dosed in the
reaction mixture; the mixture was then heated to 100 °C to react for 12 minutes; the
reaction solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous solution was
dropwise dosed until the solution was neutralized to neutral. The subsequent operation in
this example was the same as that in Example 92. The product had the deprotection
conversion rate of 92.21% or above, the radiochemical purity of 95.8% and the chemical
purity of greater than 91.1%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib
was 37.87% relative to that in the V-shaped reaction flask (the radioactivity of 1[ 8F]
Et4NOMs is usually 1.35mCi), and the specific activity (23.52Ci/ mol) was obtained from
the final preparation).
[00477] Example 123
[00478] Similar to the method of Example 122, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-PMP-5-Larotrectinib. The product had the deprotection rate of 93% and the
radiochemical purity of greater than 95.5% and chemical purity of greater than 91.5%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 37.65% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (23.81Ci/ mol) was obtained from the final preparation).
[00479] Example 124
[00480] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-MOM-2-Larotrectinib.
O N'-N OMOM F NN OMOM H \ OMOM 0 18 H, 0 F F HN 2 0 0 H C36H 40FIN 6 07 :814.65 C2 3H 26FO0 FI N 6 3:471.50 / -N MOM-2-Larotrectinib 1(1-SPIAdF- OMOM-N 8 1 F-MOM 2-Larotrectinib H
187 N N N F F
/ - N~ OMOM N OH 18 18F F (~ N FI
0 0
8 C 23 H 26FIOF1N 60 3:471.50 C 23H 24 F' F1N 6 02:427.45 18 18 F- MOM-2-Larotrectinib F- 2-Larotrectinib
[00481] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-MOM-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight condition until TLC tracked that the labeled precursor I(III)-SPIAd-MOM-2-Larotrectinib basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product 1[8 F]-MOM-2-Larotrectinib.
[00482] 6N hydrochloric acid (0.0033mmol, 0.65mg) was dosed in the reaction
mixture; the mixture was then heated to 80 °C to react for 12 minutes; the reaction
solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous solution was dropwise
dosed until the solution was neutralized to neutral. The subsequent operation in this
example was the same as that in Example 92. The product had the deprotection conversion
rate of 92.4% or above, the radiochemical purity of 95.2% and the chemical purity of
greater than 91.4%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was
36.35% relative to that in the V-shaped reaction flask (the radioactivity of 1[ 8F] Et 4NOMs
is usually 1.35mCi), and the specific activity (22.12Ci/ mol) was obtained from the final
preparation).
[00483] Example 125
[00484] Similar to the method of Example 124, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-MOM-5-Larotrectinib. The product had the deprotection rate of 93% and the
radiochemical purity of greater than 95.8% and chemical purity of greater than 91.8%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 36.25% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (22.27Ci/ mol) was obtained from the final preparation).
[00485] Example 126
[00486] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-MEM-2-Larotrectinib.
0 N'-N OMEM N OMEM H 18FOME
N N H t N N61F
1 H C 38H44FIN 6 0S:858.71 C 25H 30F FIN 6 04:515.55 1 I(Ill)-SPIAd - MEM-2-Larotrectinib F-MEM-2- Larotrectinib
18F NN18FNN6$ tHN N N H/J K$I N6
0 O 1 C 25H 30F FIN 604 :515.55 C 2 3H24 FsFIN 6 O2:427.45 18 1 F- MEM-2-Larotrectinib F- 2-Larotrectinib
[00487] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-MEM-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-MEM-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-MEM-2-Larotrectinib.
[00488] Magnesium bromide (0.0033mmol, 0.6mg) was dosed in the reaction
mixture; the mixture was then heated to 155 'C to react for 10 minutes; the reaction
solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous solution was dropwise
dosed until the solution was neutralized to neutral. The subsequent operation in this
example was the same as that in Example 92. The product had the deprotection conversion
rate of 96.7% or above, the radiochemical purity of 96.3% and the chemical purity of
greater than 96.2%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was
37.29% relative to that in the V-shaped reaction flask (the radioactivity of 18
[ F] Et 4NOMs
is usually 1.35mCi), and the specific activity (23.14Ci/ mol) was obtained from the final
preparation).
[00489] Example 127
[00490] Similar to the method of Example 126, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-MEM-5-Larotrectinib. The product had the deprotection rate of 97% and the
radiochemical purity of greater than 96% and chemical purity of greater than 96%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 37.25% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (23.21Ci/ mol) was obtained from the final preparation).
[00491] Example 128
[00492] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursor I(III)-SPIAd-THP-2-Larotrectinib.
O N'N O 0
H 0.HO - a N N
H 0 0 18 H C3 9 H4 4 FIN6 0 7SI:854.72 C 2 H30F FIN 6O3:511.56 I(lll)-SPIAd -THP-2-Larotrectinib isF-THP- 2-Larotrectinib
0O0 N'-N OH 5,N'-N
0OH 1 1 C2 6H 30F sFIN 60 3:511.56 C 23H2F sFIN1O2 :427.45 18 18 F-THP-2- Larotrectinib F- 2-Larotrectinib
[00493] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-THP-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-THP-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-THP-2-Larotrectinib.
[00494] P-toluenesulfonic acid (0.0033mmol, 0.56mg) was dosed in the reaction
mixture; the mixture was then heated to 155 °C to react for 5 minutes; the reaction
solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous solution was dropwise
dosed until the solution was neutralized to neutral. The subsequent operation in this
example was the same as that in Example 92. The product had the deprotection conversion
rate of 97.5% or above, the radiochemical purity of 98.2% and the chemical purity of
greater than 96.4%. The uncorrected radiochemical yield of [ 18F]-Larotrectinib was
41.32% relative to that in the V-shaped reaction flask (the radioactivity of 1[ 8F] Et 4NOMs
is usually 1.35mCi), and the specific activity (27.04Ci/ mol) was obtained from the final
preparation).
[00495] Example 129
[00496] Similar to the method of Example 128, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-THP-5-Larotrectinib. The product had the deprotection rate of 97% and the
radiochemical purity of greater than 99% and chemical purity of greater than 97%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 41.55% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (27.81Ci/ mol) was obtained from the final preparation).
[00497] Example 130
[00498] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-EE-2-Larotrectinib.
0 N O O 0 N'N O 18 H F
aHN
18 H C 3SH44FIN6O 7:842.71 C 25H 30F FIN 60 3:499.55
I(lll)-SPIAd -EE-2-Larotrectinib 1sF-EE- 2-Larotrectinib
1-N O N OH
1F N N6F N N6
O O 1 18 C 25H 30F FIN 603:499.55 C23 H24F FIN 602:427.45 18 18 F-EE- 2-Larotrectinib F-2- Larotrectinib
[00499] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-EE-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-EE-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was detected that there was the labeled product [ 18F]-EE-2-Larotrectinib.
[00500] P-toluenesulfonic acid (0.0033mmol, 0.56mg) was dosed in the reaction
mixture; the mixture was then heated to 155 °C to react for 5 minutes; the reaction
solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous solution was dropwise
dosed until the solution was neutralized to neutral. The subsequent operation in this
example was the same as that in Example 92. The product had the deprotection conversion
rate of 99.8% or above, the radiochemical purity of 99% and the chemical purity of greater
than 99%. The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 45.14%
relative to that in the V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is
usually 1.35mCi), and the specific activity (28.23Ci/ mol) was obtained from the final
preparation).
[00501] Example 131
[00502] Similar to the method of Example 130, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-EE-5-Larotrectinib. The product had the deprotection rate of 100% and the
radiochemical purity of greater than 99% and chemical purity of greater than 99%. The
uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 45.50% relative to that in the
V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi), and the
specific activity (28.51Ci/ mol) was obtained from the final preparation).
[00503] Example 132
[00504] Labeled product [ 18F]-2-Larotrectinib was prepared from the labeled
precursorI(III)-SPIAd-Als-2-Larotrectinib.
F F 0 0
0 N 5 N ~ H N8F N1F N N
H 0 O 1 H C37H 40FIN 6 08 S:874.72 C24H6F SFIN 6O 4 S:531.57 |(Ill)-SPIAd -Als-2-Larotrectinib l(lll)-SPIAd -Als-2-Larotrectinib
F F 0
-_N OS NN OH 18F NJN 18F
0 0 18 C24 H26 F FIN 6 04 S:531.57 C 2,H 24FlsFIN102 :427.45 1 |(Ill)-SPIAd-Als-2-Larotrectinib aF-2-Larotrectinib
[00505] According to the preparation process of labeled product [ 18F]-Larotrectinib,
anhydrous DMF-dissolved [ 18F]Et4NOMs solution (20mg/mL, 0.4mL) was prepared.
400uL of sample was separated from the above DMF solution and dosed in a V-shaped
reaction flask containing the white solid labeled precursor
I(III)-SPIAd-Als-2-Larotrectinib (1.0mg) (the radioactivity of [ 18F]Et 4NOMs is usually
1.35 mCi). The mixture was heated to 155 °C and reacted for 12 minutes under an airtight
condition until TLC tracked that the labeled precursor I(III)-SPIAd-Als-2-Larotrectinib
basically disappeared; radio-TLC tracked reaction mixture sampling (1-2uL) and it was
detected that there was the labeled product [ 18F]-Als-2-Larotrectinib.
[00506] Morpholine and 35% formic acid solution (1:1, 1.84mg) were dosed in the
reaction mixture, and a catalytic amount of palladium tetraphenylphosphorus was then
dosed; the mixture was then heated to 80 °C to react for 8 minutes; the reaction solution was cooled in a 0 °C ice bath; 10% NaHCO3 aqueous solution was dropwise dosed until the solution was neutralized to neutral. The subsequent operation in this example was the same as that in Example 92. The product had the deprotection conversion rate of 99% or above, the radiochemical purity of 96.5% and the chemical purity of greater than 96.7%.
The uncorrected radiochemical yield of [ 18F]-2-Larotrectinib was 41.54% relative to that
in the V-shaped reaction flask (the radioactivity of [ 18F] Et4NOMs is usually 1.35mCi),
and the specific activity (26.72Ci/ mol) was obtained from the final preparation).
[00507] Example 133
[00508] Similar to the method of Example 132, labeled product
[ 18F]-5-Larotrectinib was prepared from the labeled precursor
I(III)-SPIAd-Als-5-Larotrectinib. The product had the deprotection rate of greater than
99% and the radiochemical purity of greater than 97% and chemical purity of greater than
97%. The uncorrected radiochemical yield of [ 18F]-5-Larotrectinib was 41.75% relative to
that in the V-shaped reaction flask (the radioactivity of [ 18F] Et 4NOMs is usually 1.35mCi),
and the specific activity (26.71Ci/ mol) was obtained from the final preparation).
Unless the context clearly requires otherwise, throughout the description and the
claims, the words "comprise", "comprising", and the like are to be construed in an
inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense
of "including, but not limited to".
Claims (14)
1. A [1 8 F]-labeled Larotrectinib compound, comprising a 1[ 8 F]-Larotrectinib compound
having the following structural formula and its analogs:
F 18 F
-N OH -N OH 18 F (R) N HF (R) N HN N HN N
1 0 2 0 18 18 F-2-Larotrectinib F-5-Larotrectinib
18F-2-Larotrectinib 18F-5-Larotrectinib
18 F
R1(2) OH R1(2) N N OH
18 P'R) N K$ HN N HN
3 0 4 18 18 F-2-Larotrectinib analogues F-5-Larotrectinib analogues
18F-2-Larotrectinib analogues 18F-5-Larotrectinib analogues
wherein R1(2) signifies an R Iand/or R2 group, wherein R Iand R2 each
independently represent a phenyl substituent, RI and R2 are each independently selected
from group consisting of H, halogen, hydroxyl, nitro, alkyl with 1 to 6 carbon atoms,
alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to
carbon atoms, aryl with 6 to 10 carbon atoms, heterocycloalkyl with 4 to 10 carbon
atoms, and heteroaryl with 6 to 10 carbon atoms.
2. A preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 1, wherein the method comprises the following steps:
step 1: hydroxyl protection: protection of the active hydroxyl group of an
iodo-Larotrectinib analog precursor (I-Larotrectinib); step 2: preparation of a labeled precursor: carrying out iodine activation on the iodo-Larotrectinib analogue precursor (I-Larotrectinib)with the activated active hydroxyl group in step 1 to prepare a trifluoroacetic acid I-Larotrectinib analogue, and then causing the trifluoroacetic acid I-Larotrectinib analogue to react with an adamantane-substituted auxiliary acid to prepare a labeled precursor: hydroxy-protected spirocyclic hypervalent
I(III)-Larotrectinib analogue; and
step 3: preparation of 18F-labeled product: carrying out substitution reaction of the
labeled precursor with a 18F radioactive source to prepare hydroxyl-protected
18F-Larotrectinib and synthesize a 18F-Larotrectinib analog, and then carrying out
deprotection to obtain 1 8 F-Larotrectinib and a 18F-Larotrectinib analogue.
3. The preparation method of the 1[ 8 F]-labeled Larotrectinib compound according to
claim 2, wherein the I-Larotrectinib analogue precursor in step 1 has the following
structural formula:
R1 R N'N OR3
(R) N
in the above formula, RI and R2 each independently represent a phenyl substituent,
RI and R2 are each independently selected from group consisting of H, halogen, hydroxyl,
nitro, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6
carbon atoms, cycloalkyl with 3 to 10 carbon atoms, aryl with 6 to 10 carbon atoms,
heterocycloalkyl with 4 to 10 carbon atoms, and heteroaryl with 6 to 10 carbon atoms;
in the above formula, R3 specifically represents H;
the protection of the active hydroxyl functional group means that through esterification
or etherification, R3 is substituted with the following functional groups to protect the
active hydroxyl, and the substituted functional groups include trimethylsiloxane (TMS),
tert-butyldimethylsiloxane (TBDMS), triethylsiloxane (TES), tert-butyldiphenylsiloxane
(TBDPS), methyl ether (Me), benzyl ether (Bn), trityl ether (Tr), p-methoxytrityl ether
(MMT), dimethoxytrityl ether (DMT), tert-butyl ether ( tBu), methoxy methyl ether
(MOM), 2-methoxy ethoxy methyl ether (MEM), methylthio methyl ether (MTM),
benzyloxy methyl ether (BOM), p-methoxybenzyl ether (PMB), p-methoxybenzyloxy
methyl ether (PMBOM), 3,4-dimethoxybenzyl ether (DMB), tetrahydropyran ether (THP),
methoxycarbonyl (Moc), ethoxycarbonyl (Eoc), tert-butoxycarbonyl (Boc),
benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl (Ac),
trifluoroacetyl (TfAc), chloroacetyl Base (CAc), dichloroacetyl (DCAc), benzoyl (Bz),
pivaloyl (Pv), methanesulfonyl (Ms), benzylsulfonyl (Bs), allylsulfonyl (Bs), allyl
Alkyloxycarbonyl (Als), allyloxycarbonyl, alkanoyl with 1 to 16 carbon atoms,enoyl with
2 to 16 carbon atoms, alkynyl with 3 to 6 carbon atoms, cycloalkyl with 4 to 10 carbon
atoms, aroyl with 7 to 16 carbon atoms, and heterocycloalkanoyl with 4 to 10 carbon
atoms; alkanoyl is preferably acetyl; the aroyl is preferably benzoyl; the substituted
alkanoyl is pivaloyl or phenylacetyl.
4. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 2 or 3, wherein the I-Larotrectinib analogue precursor in step 1 has the following
structural formula:
F
NN OH N OH FN '
0 0
I 2-Lartrat~rnIb |I5.Lvotteetinib or 5. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 4, wherein step 1 is to substitute the active hydroxyl in the I-Larotrectinib analog
precursor to achieve protection, and the substitution method comprises:
(1) benzoyl chloride esterification based on the following reaction formula:
F F
00
C 21H 22F1N 60 2: 536.35 C 2gH 26FIN 60 3:640.46 1-2- Larotrectinib I - Bz-2-Larotrectinib
or,
00
C 21H2 2F1N 602 : 536.35 C 28H 26 FING0 3:640.46 1-5- Larotrectinib I - Bz-5-Larotrectinib
(2) pivaloyl chloride esterification based on the following reaction formula:
F OH O F -N 00
00
C2 1H2 2FIN 602 : 536.35 C 26H 30FING0 3:620.47 I -5-Larotrectinib I -Piv-5-Larotrectinib
F F
OH ~NN
C 2 1H22 F1N6 02 : 536.35 C2 32 FIN 603 :620.39 I -2-Larotrectinib I -Aci--Larotrectinib
(3)acty cloid eteifiatonbaedonth fllo in racio 123la or, N 0
F F
- N N6 CF
I H-fa N2 N J 02
C2 1 H22 F1N6 0 2 :536.35 C2 3H2 F1N6 0 3:532.39 I -2-Larotrectinib I -T--Larotrectinib
F F 0
:P N OH N N, 0 CF3
0 2 0
C2 1 H22 F1N6 02 : 536.35 C23H2 1F41N6 03:632.36 I -5-Larotrectinib I -Tf-5-Larotrectinib
F F
N N6
C 21 H22 FN 6 02 : 536.35 C 23 23 F612.3:62 I -- Larotrectinib IIcTf-2-Lo rtnlb ni
F F
9'NN OH OOCCHCCHCI
C 21 H22 F1 6 02 :536.35 23C23NG H23 C618 3 :628 I--Larotrectinib I -CAc-5-Larotrectinib
(6dco raerchoieseiaiobsdnhfloinratofrua
®rx-"N OHN OOC124
F F
~N ~N ~ 00N OH 51 > 00' N N\CCC
HN-rNHN 0 0 C2 1 H 22 F][N 60 2 : 536.35 C2 3H 2 2 C12 F1N 6 0 3 :647.27 1-2- Larotrectinib I-DCAc -2- Larotrectinib
or,
\ OOCCHC1
aN 0"~ N~ OH' ,OI 2
0N HN N 0 0 C 21 H22 F1N 6 02 : 536.35 C23 H22 C12 FIN 6 03 :647.27 1-5- Larotrectinib I-DCAc -5- Larotrectinib
(7) methyl chioroformate esterification based on the following reaction formula:
F OF0
N OH N- N 0A
HN HN N-&
C 21 H22 FIN6 02 : 536.35 C2 3H 24FIN 60 3:594.39 I --2-Larotrectinib I -Moe-2-Larotrectinib
or,
NNi~ OH N
F F
NN N6
HN N6HN N
C2 1H2 2FN6 02 : 536.35 C 2 H2 FN0:60.41 I -- LarotrectinibI- o5Latrcnb
(8 ehy cloofrmteeserfiatonbse o te olowngrecto1fomua aN FNN N H F NON O FF
1 2 0
C 21H 22FIN 60 2: 536.35 C24 H2 6FIN 604:608.41 I - 5-Larotrectinib I - Eoc-5-Larotrectinib
(9) Boc anhydride esterification based on the following reaction formula:
F F
N.N OH N'N OBoc
NNN N
C 21H 22FIN 602 : 536.35 C 2GH 30FIN 604: 636.47 1 - 2-Larotrectinib I - Boc-2-Larotrectinib
(10) 2,2,2-trichloroethyl chloroformate (Troc) esterification based on the following
reaction formula:
I ~0-'\N CCI 3 F N OH N O
N6 N HN §N 0K a NKL> NNIO C
C 21H22FIN 6 02: 536.35 C 24H 23C13FIN 604:711.74 I - 2-Larotrectinib I -Troc-2-Larotrectinib
(11) trimethylsilyl ethoxycarbonyl chloride (Teoc) esterification based on the
following reaction formula:
F F 0
-N OH -N 0 OA
N NS
O O C 21 H22 FIN 6 02 :536.35 C 27 H 34 FIN 6 04Si:680.59 I-2-Larotrectinib I -Teoc-2-Larotrectinib
(12) tert-butyldimethylchlorosilane etherification based on the following reaction
formula:
F F
NN OTB
S NN OH
N N6
C 27H 36FING0 2Si:650.61 C21H 22FIN 60 2:536.35 I - 2-Larotrectinib I -TBS-2-Larotrectinib
(13) triisopropylchlorosilyl etherification based on the following reaction formula:
F F
N-'N OTIPS -N OH
_ _ N
C 21H 22FIN 602 : 536.35 C30 H42 FIN 602Si:692.69 I - 2-Larotrectinib I - TIPS-2-Larotrectinib
(14) tert-butyldiphenylchlorosilane etherification based on the following reaction
formula:
F F
-N OH N'N OTBDPS
0 C' HN N N
C 21H 22FIN 6 02: 536.35 C37 H4 0FING0 2Si:774.75 I - 2-Larotrectinib I - TBDPS-2-Larotrectinib
(15) P-methoxybenzyl etherification (PMB-(p-Methoxybenzyl)ether) based on the
following reaction formula:
F F OMe
N OH / - N 0
N N N6
10
C 21H 22FIN 602 : 536.35 C29 H 30FIN03:656.50 I - 2-Larotrectinib I - PMB-2-Larotrectinib
(16) P-methoxymethyl etherification (MOM) based on the following reaction formula:
F F
OH - -N OMOM .- N
N N, N NN K 6
1 02 0
C21H 22 FIN60 2 : 536.35 C 23H 2 6FIN 6 03:580.40 I - 2-Larotrectinib I - MOM-2-Larotrectinib
(17) methoxyethoxymethyl chloride etherification based on the following reaction
formula:
F F
N.-N OMEM N OH
N
1 N a~N6 2 0
C 21H22FIN 602 : 536.35 C 25H30FIN 604 :624.46 1 -2- Larotrectinib I - MEM-2-Larotrectinib
(18) 2-(trimethylsilyl)ethoxymethyl chloride etherification based on the following
reaction formula:
F F
'N.N OH N 0 0
NN N6s
C 21 H 22 FIN 6 02 :536.35 C27 H 36FIN 6 0 3 Si:666.61 I - 2-Larotrectinib I -SEM-2-Larotrectinib
(19) tetrahydropyran etherification based on the following reaction formula:
F F 0 OH / OH N...N 00 O , .- N
N N N N6
1 02 0
C 21 H22 FIN 60 2 : 536.35 C 26H30FIN 603 :620.47 I - 2-Larotrectinib I -THP-2-Larotrectinib
(20) 1-ethoxyethanol acetate (EE) etherification based on the following reaction
formula:
F F
,N OH N'- O
0~ 0 N6 N HN-f NOrN O o
C 21H 22FIN 60 2: 536.35 C 25 H 30FING0 3:608.46 I - 2-Larotrectinib I -EE-2-Larotrectinib
(21) allyl sulfonyl chloride etherification based on the following reaction formula:
F F
N OH N.~N OI
00 N N6 0N( N
C 21H 22FIN 6 02: 536.35 C 24H2 6FIN 604S:640.47 I - 2-Larotrectinib I - Als-2-Larotrectinib
(22) P-methoxyphenol etherification (PMP-(p-Methoxyphenyl)ether) based on the
following reaction formula:
F F OMe
OH -N N
NIN NNN
10
C 21H 22FIN 602 : 536.35 C2 8H2 8FIN03:642.47 I - 2-Larotrectinib I - PMP-2-Larotrectinib
6. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 2, wherein the preparation of the trifluoroacetic acid iodo-Larotrectinib analogue in
step 2 is to cause the iodo-Larotrectinib analog precursor (I-Larotrectinib) with protected
active hydroxyl prepared in step 1 to react with trifluoroacetic acid or trifluoroacetic
anhydride, an organic solvent and an oxidant so that I is activated by trifluoroacetate;
the organic solvent comprises one or more of chloroform, dichloromethane,
acetonitrile, acetone, and tert-butanol peroxide;
the oxidant comprises a urea-hydrogen peroxide complex, Oxone,
2,2,6,6-tetramethylpiperidine-oxideormCPBA.
7. The preparation method of the 1[ 8 F]-labeled Larotrectinib compound according to
claim 2, wherein the adamantane-substituted auxiliary acid in step 2 is SPIAd, and the
conditions for the reaction of SPIAd with the trifluoroacetic acid iodo-Larotrectinib analog
are as follows: SPIAd is mixed with one or more of sodium carbonate solution, MeCN,
NaHCO3 and acetone at 0°C, and the pH of the mixed solution is controlled to be 8 to 10,
and the mixed solution reacts with the trifluoroacetic acid iodo-Larotrectinib analogue at
°C while continuously stirring for 1 hour to 10 hours, thus obtaining the labeled
precursor.
8. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 2, wherein the preparation of the labeled precursor in step 2 specifically follows the
following methods:
(1) preparation of labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib or
I(III)-SPIAd-Bz-5-Larotrectinib based on the following reaction formula:
F F
N OOCC6 H5 N'-N OOCCsHs
N N N HNCS
O 0 C 28H 26FING0 3:640.46 C3 2 H 2WFylN 6 0 7 :868.50
I - Bz-2-Larotrectinib I -TfAc- Bz-2-Larotrectinib and F F
CO N-N OOCCSH 0 / N-N OOCCH,
F 3 CCOO N HN6 O N6
0 ''11H 0 Ca2H 2 FylN0 7:868.50 H C41 H42FIN 60 7:876.72 I-TfAc- Bz-2-Larotrectinib I(III)-SPIAd - Bz-2-Larotrectinib
(2) preparation of labeled precursor I(III)-SPIAd-Piv-2-Larotrectinib or
I(III)-SPIAd-Piv-5-Larotrectinib based on the following reaction formula:
F F
I ~ N N F3CCOO a N(N HN 1§N
0 0 C 26H 30 FIN 60 3:620.47 C 30H-30 F 7 1N 607: 846.50 1- Piv-2-Laratrectinib I - Piv-TfAc-2-L-arotrectinib
F F 0 0
F3 CCOON-H\ F 3CCOO -N H
a N KI C30H-30F 7 1N607:846.80 H C39 H-44FIN6O7: 854.72 1 -Piv-TfAc-2-L-arotrectinib I(111-SPIAd -Pl-2-Larotrectinib
(3) preparation of labeled precursor I(III)-SPIAd-Ac-2-Larotrectinib or
I(III)-SPIAd-Ac-5-Larotrectinib based on the following reaction formula:
F F 0 0
-N N / 5- N C H F3CCOO-. 1 -J H N FCCOO N'T HN N, HN
0 0 C 23H 2 4FINS0 3 :578.39 C 27H 24 F 71N07 :804.42 I -Ac-2-Larotrectinib I -Ac-TfAc-2-L-arotrecti nib
F F 0 0
F3CCOO-I1 CH3 H1'I KIC~ H3 N N6H9 o~ HN- N
C27H 24F 71N 607: 804.42 H C36H 38FIN 607:812.64 I -Ac-TfAc-2-L-arotretinib I(111-SPIAd -Ac -2- Larotrectinib
(4) preparation of labeled precursor I(III)-SPIAd-Tf-2-Larotrectinib or
I(III)-SPIAd-Tf-5-Larotrectinib based on the following reaction formula:
F F 0 0
C 3 F 3CCOO... F 7>NHN N,( ~F 0/ 3CCOO ~ HN.-
0 0 C 23 H-2 1F 41N 603 :632.36 C 27H 23 CIF1N07 : 838.86 1- Tf-2-Larotrectinib I -Tf-TfAc-2-L-arotrectinib
F F 0 0
F 3CCOO 1 N N N'N HN N OA C ______
F H H O N N'N 0 $CF C 3
H OHN N6 F
O ?,'H 0O C 27H 21F 1 0|N 607: 858.39 H C 36H 3 F4 1NO07: 866.61 1 - Tf-TfAc-2-Larotrectinib |(Ill)-SPIAd -Tf -2-Larotrectinib
(5) preparation of labeled precursor I(III)-SPIAd-CAc-2-Larotrectinib or
I(III)-SPIAd-CAc-5-Larotrectinib based on the following reaction formula:
F F
/ N N OOCCH 2CI N -N OOCCH 2CI - F 3 CCOO N N FCCOO N N
0 0 C 23H 23CIFIN 603: 612.83 C 27H 23CIFIN 607: 838.86 1 -CAc-2-Larotrectinib I - CAc-TfAc-2-Larotrectinib
F F
N'N OOCCH 2CI 0 N'N OOCCH 2CI
F3CCOO 7 N 0IIJN H4 K HN FT HN 0 "' C 27H 23CIFIN0 7: 838.86 H C36H 3yCIFIN 6 07: 847.08 1 -CAc-TfAc-2-Larotrectinib |(Ill)-SPIAd -CAc - 2-Larotrectinib
(6) preparation of labeled precursor I(III)-SPIAd-DCAc-2-Larotrectinib or
I(III)-SPIAd-DCAc-5-Larotrectinib based on the following reaction formula:
F F
0 NN OOCCHC1 2 NN OOCCHC1 2
N N FF 3 CCOO N N
C 2 3H 22 C 2 FIN 6 03: 647.27 C 2 7H 22C 2 F 7 1N0 7: 873.30 1 - DCAc-2-Larotrectinib I - DCAc-TfAc-2-Larotrectinib
F F
S- N' OOCCHCl2 0 -N OOCCHC1 2
F3CCOO N N H HO N N6
7 60 7: 873.30 C27H 22 C12F yN C36 H 36C12FIN 60 7: 881.52 1 - DCAc-TfAc-2-Larotrectinib H I(Ill)-SPIAd - DCAc-2-Larotrectinib
(7) preparation of labeled precursor I(III)-SPIAd-Moc-2-Larotrectinib or
I(III)-SPIAd-Moc-5-Larotrectinib based on the following reaction formula:
F F 0 0
- ~FCCOO- 1
cIN N HN-W N FCCOO I N N6 N6 ~HN 0 0
C 23 H2 4FINr 604 :594.39 C 27H 40 F 7 1N: 842.66 1- Moc-2-Larotrectinib I - Moc-TfAc-2-Larotrectinib
F F 0 0
F3CCOO-~ N- -S. 0 H 0 0- 51N-N N 0AO
' F3CCOO' N N62'0- \iHN6
C27H 40 F 71N:842.66 H C3,H 39FINGOS: 828.64 1-Moc-TfAc-2-Larotrectinib I(111-SPIAd -Mc -2-Larotroctinib
(8) preparation of labeled precursor I(III)-SPIAd-Eoc-2-Larotrectinib or
I(III)-SPIAd-Eoc-5-Larotrectinib based on the following reaction formula:
F F 0 0
-~N0\ F3CCOO-I
KjNN F3N KIYN3
C 24H 26 FIN 60 4:608.41 C 28 H 26F 7IN 6 0: 834.44 1-Eoc-2-Larotrectinib I - Eoc-TfAc-2-Larotrectinib
F F 0 -. 0
N N F 3CCOO. 3'~ F3CCOO' nXINN
C28H26F 7 1N60g:834.44 H C37H40FINS0O 8 842.66 1- Eoc-TfAc-2-Larotrectinib I(111-SPIAd -Eoc -2-Larotrectinib
(9) preparation of labeled precursor I(III)-SPIAd-Boc-2-Larotrectinib or
I(III)-SPIAd-Boc-5-Larotrectinib based on the following reaction formula:
F F
/~N ~ OBoc 0 /- N OBoc
H IN N6
KJ HN H, 0 0
C 26H3oFINGO4 : 636.47 H C 39 H 44FN0: 870.72 1- Boc-2-L1arotrectinib I(11)-SPIAd - Boc-2-L1arotrectinib
(10) preparation of labeled precursor I(III)-SPIAd-Troc-2-Larotrectinib or
I(III)-SPIAd-Troc-2-Larotrectinib based on the following reaction formula:
/C1 < - 0--\'~ CC 3 ---- I.- F 3 CCOO..1 N N6F 3CCOO N N HN- NH
0 0 C24 H23Cl 3FIN 60 4:711.74 C 28 H23 C13 F7 11N 6 08 :937.77 I -Troc-2-L1arotrectiriib I -Troc-TfAc-2-L1arotrectinib
F
/ ~ CC 3 F3CCOO- 1 H N 7 0 C2 RH23CI 3F 7 IN6 0 :937.77 H C37 H 37 CI 3FIN~ 6 O8 :945.99 I -TrocTfAc-2-L1arotrectinib I(11)-SPAd -Troc-2-L-arotrectlnlb
(11) preparation of labeled precursor I(III)-SPIAd-Teoc-2-Larotrectinib or
I(III)-SPIAd-Teoc-5-Larotrectinib based on the following reaction formula:
F 0 F0
Ic\ N \/ ' N N IN HN.¶)( I<KSj F3CCOO N HN-Si-I 0 0 C 27 H3 4 FIN 6 O4 Si:680.59 C 3 jH 34 F7 1N 6 0 8 Si:906.63 I -Teoc-2-L1arotrectinib I -Teoc-TfAc-2-L1arotrectinib
F F 0 0
F3CCOO~ NoK S N6~ ~ KI JN N HN N' HN-N C3 jH 36 F7 1N 6 07 Si:892.64 H C 4 0]H 4sFLN 6 OsSi:914.85 I -Teoc-TfAc-2-L1arotrectnib I(11)-SPIAd -Teoc-2-L-arotrectinib
(12) preparation of labeled precursor I(III)-SPIAd-TBS-2-Larotrectinib or
I(III)-SPIAd-TBS-5-Larotrectinib based on the following reaction formula:
TSF 5 'NN OB OF NN
I "' / N~ OTBSF 3 CCOO-.OB N- N6 HN N6 3CCO HNF
C 27H 36FIN 602 S!:650.61 C3 1H 36F 7 N 606 S:876.64 1-TBS-2-Larotrectinib I -TBS-TfAc-2-Larotrectinib
F F
3 CO~' N OTBS 0 N OTBS FCCOOH I F3QIJN NN6N N6 C 31H 36F 71NO0 6S: 876.64 H C 40H 50FIN 60 6S: 884.86 1- TBS-TfAc-2-Larotrectiriib I(111-SPIAd -TBS -2-Larotrectinib
or,
/ N ~ OTBS 0 /N OB
N N HN HN, N6
C 27H 36FIN 602S1:650.61 H C 40 Hr 0F1N 60 6Si: 884.86 1-TBS-2-Larotrectinib I(111-SPIAd -TBS -2-Larotrectinib
(13) preparation of labeled precursor I(III)-SPIAd-TBDPS-2-Larotrectinib or
I(III)-SPIAd-TBDPS-5-Larotrectinib based on the following reaction formula:
F F
-$N OTBOPS /N OTD a N K S F3CCO% N
C 37H 40FIN 60 2S:774.75 C4 1H 4 0F 7 N 60 6S: 1000.79 1-TBPS-2-Larotrectinib I -TBPSTAc-2-Larotrectinib
F F
F /~N TBP H I / N OTBDPS 3CCOO-~
F3CCOO () N HN--,4 0 H0 N-'i HN N6
C41 H-40F 7INSOGSE 1000.79 H C 50H-15FINGOGSi: 1009.01 1- TBD)PS-TfAc-2-L-arotrectinib I(11)-SPIAd -TBDPS -2-Larotrectinib
(14) preparation of labeled precursor I(III)-SPIAd-TIPS-2-Larotrectinib or
I(III)-SPIAd-TIPS-5-Larotrectinib based on the following reaction formula:
F F
S - N ~ OTIPS FCO /NN OTIPS
a N N
0 F 3 CCO0
(ZCO 0 N C 30 H-14FIN 60 2S":92.69 C34H14F7IN 6 Si:t918.72 1- TIPS-2-Larotrectinib I -TIPS-TfAc-2-Larotrectinib F F
3 CO. N -N/ OTIPS -0 NN ~ OTIPS 3CCOOH I N HN.( 0 0
C 34H42F 7IN 6 O6Si: 918.72 H C 43H56FlN6 O6Sl: 926.94 1- TIPS-TfAc-2-Larotrectinib I(11)-SPIAd -TIPS -2-Larotrectirlib
(15) preparation of labeled precursor I(III)-SPIAd-PMB-2-Larotrectinib or
I(III)-SPIAd-PMB-5-Larotrectinib based on the following reaction formula:
F OMe F t\, OMe
F3CCOO-.. N N6 ~ N6N F 3CCOO <jj
C 33H3 OF7 flN 6 O7 :882.53 C29H 30FINS0 3:656.50 I - PMB1-TfAc-2-L-arotrectinib I -P1MB-2-L-arotrectlnlb
OMe ta OMe
F3CCCOO- 0 H 1 \ F3CCOO - CN N2_____
C3 3 H3 F,1N 6 0,:882.53 H C 4 2H 4 4F1N 60 7 :890.75 I -PMB-TfAc-2-Larotreatlnlb 1(111-SPAd -MB-2-Larotrectlnlb
(16) preparation of labeled precursor I(III)-SPIAd-MOM-2-Larotrectinib or
I(III)-SPIAd-MOM-5-Larotrectinib based on the following reaction formula:
F F
N" OMOM FC O,\ -N~ OMOM
N H N6 0KuhNO N N 0 0 C 23 H2 6 F1N6 03 :580.40 C 27 H 26 F7 1N 6 07 :806.43 I -MOM-2-Larotrectinib I - MOM -TfAc-2-L-arotrectin ib
F F
ox OMOM 0 -N OMOM F3CCOO- 1 H 1 F3 CCOO ~N N N6 HNrII§ Kj HN- Ht,.0
C27 H26 F 7 1N 6 07 :806.43 H C36H 40 FIN'6 O7 :814.65 I -MOM-TfAc-2-Larotrectiriib I(111)SPIAd -MOM-2-Larotrectlnb
(17) preparation of labeled precursor I(III)-SPIAd-MEM-2-Larotrectinib or
I(III)-SPIAd-MEM-5-Larotrectinib based on the following reaction formula:
F IF
N- OMEM 3 O N -~ N OMEM
HN N60 FCO HN N
C 25 H 30 FIN 6 0 4 :624.46 C 29 H3 0 F7 1N 6 08 :850.49 1-MEM-2-Larotrectinib I - MEM -TfAc-2-L-arotrecti nib
F F
F3CCOO ~ N-/ OMEM 0 / .- N~ OMEM F_ H F3CCOO c~N N N6N I a
N;~" N
C29 H 30 F7 1N 6 08 :850.49 H C 38 H44 F1N 6 0S:858.71 I -MEM-TfAc-2-Larotrectinib I(111-SPIAd -MEM-2-Larotrectinib
(18) preparation of labeled precursor I(III)-SPIAd-SEM-2-Larotrectinib or
I(III)-SPIAd-SEM-2-Larotrectinib based on the following reaction formula:
F F
N- 0 pco- 1 NN OSEM
N N6F 3 CCOO N F'>( HN-- N iNN
0 0 C27 H 36 FIN 6 O3 Si:666.61 C3 jH 36 F7 1N 6 0 7 Si:892.64 I-SEM-2-Larotrectinib I -SEM-TfAc-2-Larotrectinib
F F
F 3 CCOO~~N '/ NOEM0 / NN OSEM t FCCOO / N N6" N"L N6) N HN-, H HN-,
C3 jH36F7 1N60 7 Si:892.64 H C4 0 H59FI1N 6 O7 Si:900.86
I -SEM-TfAc-2-Larotrectinib I(111-SPIAd -SEM-2-Larotrectinib
(19) preparation of labeled precursor I(III)-SPIAd-THP-2-Larotrectinib or
I(III)-SPIAd-THP-5-Larotrectinib based on the following reaction formula:
F F
N N6ca F3CCO N; N" HN - ' HN N 0 0 C 27 H30 F11N6 03 Si:620.47 C 39 H44 F1N 6 0 7 S1:854.72 I -THP-2-Larotrectinib I -TfAc- THP-2-Larotrectinib
N 0 0o00 0 F3CCaaO F3CCOO N N N.
C39H 44FIN 6O 7S1:854.72 HC 39 ]H 44FIN 6 O 7 S1:854.72 I-TfAc- THP-2-Larotrectinib I(111-SPIAd -THP-2-Larotrectinib
(20) preparation of labeled precursor I(III)-SPIAd-EE-2-Larotrectinib or
I(III)-SPIAd-EE-5-Larotrectinib based on the following reaction formula:
F F
/-' 0 - F 3CCOO- 1 N N F 3CCOO HN-- N
0 0
C 25 H3 0FIN 603 :608.46 C2 9 H30 F1N6 0 7 :834.49 I -EE-2-Larotrectinib I -TfAc- EE-2-Larotrectinib
F F
0 0 N- - 0 F3CCOO ~CJNN ___- H N6iJ HNN
H C29]E 3gF1N 607 :834.49 C3sH44FLN 6O 7:842.71 I -TfAc- EE-2-Larotrectinib I(111-SPIAd -EE-2-Larotrectinib
(21) preparation of labeled precursor I(III)-SPIAd-Als-2-Larotrectinib or
I(III)-SPIAd-Als-5-Larotrectinib based on the following reaction formula:
F F
N O -N O OI
7 NN N6 O FaCCOO N N6 OzN
O 0
C 25H 30FING04S:656.52 C 29H 30FylNSOSS:882.55 I - Als-2-Larotrectinib I - Als-TfAc-2-Larotrectinib
F F 0
F3CCOO-.. J 1 5 0- N5 CCOO F3 N HNN
C29H30F7 NsOSS:882.55 H C 37H[4FIN6 O8S:874.72 I -Als-TfAc-2-Larotrectinib |(Ill)-SPIAd -Als-2-Larotrectinib
(22) preparation of labeled precursor I(III)-SPIAd-PMP-2-Larotrectinib or
I(III)-SPIAd-PMP-5-Larotrectinib based on the following reaction formula:
F OMe F O_ Me
\< ~ ~ F3CCOO. 1 \ -N¶
N F3 CCOO N
0 0 C 28H28FIN 6O3:642.47 C32H2sF 7IN 60 7 :868.50 I - PMP-2-Larotrectinib I - PMP-TfAc-2-Larotrectinib
F F
OMe 0NI OMe ON F3 CCOO-I 1 H I~O F3CCOO N HNN6
C3 2H 2UF71N 607:868.50 H C 4 1H 42 FIN 60 7 :876.72 I - PMP-fAc-2-Larotrectinib I(Ill)-SPIAd -PMP-2-Larotrectinib
9. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 2, wherein the 18F radioactive source in step 3 is obtained by the following method:
(1) preparation of [ 18F] fluoride target water: producing [ 18F] fluoride target water by
1 80(p,n) 18F nuclear reaction, and delivering the [ 18F] fluoride target water to a sterile
lead-protected hot cell of 180-enriched water by nitrogen pressure;
(2) enrichment of [ 18F] fluoride by QMA anion exchange solid phase extraction
cartridge (QMA): causing an aliquot of the target water containing an appropriate amount of [ 18F] fluoride to slowly pass through the anion exchange solid phase extraction cartridge (QMA) under a nitrogen flow, enriching the [ 18F] fluoride on the QMA anion exchange solid phase extraction cartridge (QMA), and removing 18O and other impurities by separation and elution, thus obtaining [ 18F] fluorine source for the [ 18F] fluoride QMA anion exchange solid phase extraction cartridge (QMA);
(3) eluting the [ 18F] fluoride enriched on the QMA anion exchange solid phase
extraction cartridge (QMA) to obtain a quaternary ammonium salt or inorganic salt
solution of [ 18F] fluoride; washing the [ 18F] fluoride enriched on QMA anion exchange
solid phase extraction cartridge (QMA) with a washing solution and eluting the [ 18F]
fluoride into a V-shaped flask sealed with a Teflon-lined diaphragm, thus obtaining an
acetonitrile aqueous solution or an acetonitrile or methanol solution of the organic or
inorganic salt of [ 18F] fluoride; and
(4) preparation of a dry quaternary ammonium salt or inorganic salt of [ 18F] fluoride:
heating the V-shaped flask containing the acetonitrile aqueous solution or acetonitrile or
methanol or ethanol solution of the organic or inorganic salt of [ 18F] fluoride and sealed
with a Teflon-lined diaphragm to 95 °C to 110 °C, and at the same time drying nitrogen
gas by passing through a P 205 -DrieriteTM column to blow the V-shaped flask, and then
discharging the exhaust gas through the vented flask; when no liquid is seen in the flask,
taking the flask out of the hot bath, dosing anhydrous acetonitrile (1 mL) in the flask, and
heating the flask again until the flask is dry; repeating this step another three times; then,
cooling the flask at room temperature under nitrogen flow, thus obtaining a dry organic or
inorganic salt of [ 18F] fluoride.
10. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 9, wherein the anion exchange solid phase extraction cartridge (QMA) in step (2) is
pre-activated by being washed with NaHCO 3(aq) and water;
the washing solution in step (3) is obtained by dissolving an organic or inorganic base in acetonitrile and water (v/v: 7:3) or acetonitrile or methanol or ethanol, and the organic or inorganic base comprises tetraethylammonium bicarbonate; the organic or inorganic salt of [ 18F] fluoride in step (4) comprises
[1 8F]KF/K 2 CO 3 /K 2 .2.2, [1 8F]KF/K2C204/K2.2.2, [1 8F]KF/KOTf, [18F]Et4NF, [ 18F]Et 4NHCO 3
,
[ 18F]Et4NOMs, and [ 18F]Et 4NOTf, and its radioactive [ 18F] fluoride recovery rate varied
depending on the elution process used.
11. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 9, wherein the substitution reaction between the labeled precursor and the 18F
radioactive source in Step 3 is implemeted by: dosing a solvent in the V-shaped flask
containing the dry organic or inorganic salt of [ 18F] fluoride to re-dissolve the dry organic
or inorganic salt, and then dosing the labeled precursor to take reaction, thus obtaining a
crude reaction solution of undeprotected labeled product [ 18F]-Larotrectinib.
12. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 9, wherein deprotection in step 3 is implemented by the following method: dosing or
not dosing a certain amount of organic base or inorganic base or organic acid or inorganic
acid in the crude reaction solution of undeprotected labeled product [ 18F]-Larotrectinib,
and removing the hydroxyl protecting group by heating, thus obtaining a crude reaction
solution of labeled product [ 18F]-Larotrectinib.
13. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 12, wherein the crude reaction solution of labeled product [ 18F]-Larotrectinib is
separated and purified by the following method: purifying the crude reaction solution of
labeled product [ 18F]-Larotrectinib by semi-preparative HPLC or Waters Sep-Pak C-18
cartridge, and rinsing the purified product with a solvent into a sterile vacuum flask, blow
drying with nitrogen at 60 'C for 20 minutes, and reconstituting a solution with brine,
wherein the obtain solution includes 100ul of 25% Vitamin C aqueous solution and 100ul
of 20% Tween 80 ethanol solution is a labeled product [ 18F]-2-Larotrectinib injection.
14. The preparation method of the [ 18F]-labeled Larotrectinib compound according to
claim 2, wherein the preparation of [ 18F]-labeled Larotrectinib from the labeled precursor
in step 3 comprises the following methods:
(1) labeled product [ 8F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Bz-2-Larotrectinib based on the following reaction formula:
F F
H N...N OOCCH! NN OOCC6 H5
00 H 18F
8 H C4 1H 42FIN 60y:876.72 C2 8H26F' FN 60 3: 531.55 8 1(Ill)-SPIAd - Bz-2-Larotrectinib F -Bz-2-Larotrectinib
O 0 0 '
F N-N OOCC 6 H 5 F NN O
1sFHN N 1JFN N
8 C2 8 H26 F' FN603 : 531.55 C21 H22 F'SFN6 0 2 : 427.45 18 F -Bz-2-Larotrectinib 'OF-2-Larotrectinib
(2) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-TBS-2-Larotrectinib based on the following reaction formula:
F F
O N'N OTBS NN OTBS H I- _
0 N 18N H
18 H C 40H 50FIN 606Si:884.86 C 27 HaF FN602 Si:541.71 18 |(Ill)-SPIAd -TBS - 2-Larotrectinib F -TBS-2- Larotrectinib
F F
ISF 18 F N N N -H N N N 1s OTBS
8 8 C2 7H 3,F' FN6 O2 Si:541.71 C 21 H22F' FNI02:427.45 18 18F -TBS-2- Larotrectinib F - 2-Larotrectinib
(3) labeled product [ 8F]2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-SEM-2-Larotrectinib based on the following reaction formula:
FF
o N'N OSEM N -N OSEM Ha H, 18F
H C 4 0H 50 FIN 60 7 Si:900.86 C 2 7H 36FIOFN 60 3 Si:557.71
F (Ill)-SPIAd - SEM-2-Larotrectinib OF -SEM- 2-Larotrectinib
18 N-N OSEM 1 N-N OH F sF
CH N Nr N§ 18 C 2 7 H 36F FN6 0 3 Si:557.71 C 2 1H 2 2 F1'FN6 0 2 : 427.45 1 18 F -SEM- 2-Larotrectinib F -2- Larotrectinib
(4) labeled product [ 18F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-TBDPS-2-Larotrectinib based on the following reaction formula:
F F
0 /--N OTBDPS - -N OTBDPS
H 19F
H H H,,, N6 H 0 0 19 H Cs 0H 54FIN 60 6Si:1009.01 C 37H 4oF FIN 602Si:666.85 |(Ill)-SPIAd -TBDPS -2- Larotrectinib 19 F -TBDPS-2-Larotrectinib
F F
N...N OTBDPS N OH
19F N FN
C37H 40F19FIN 602Si:666.85 C 21H 22F' FIN 602 :428.44 19 19 F -TBDPS-2-Larotrectinib F -2- Larotrectinib
(5) labeled product [ 8F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-TIPS-2-Larotrectinib based on the following reaction formula: F F
H NN OTIPS -N OTIPS N
H 19F 00
9 H C 43HssFIN 6OSSi:926.94 C1 7H 4 2 F' FIN10 2 Si:584.79 |(Ill)-SPIAd -TIPS - 2-Larotrectinib 1 9F -TIPS-2-Larotrectinib
F F
N -N OTIPS . OH 19 19F N F
19 C37 H42F'OFIN10 2Si:584.79 C 21H 22F F1N 6 02 :428.44 19F -TIPS-2-Larotrectinib 19F - 2-Larotrectinib
(6) labeled product [ 18F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Teoc-2-Larotrectinib based on the following reaction formula:
F F 0o
0 ax
H C 40 H48 F1N6 08 Si:914.85 C 27 H 34 F'SFN 604 Si:571.69 18 I(111-SPAd -Teoc-2-Larotnectinib F -Tooc- 2-Larotrectinib
FF
18 'N -N F ;' OH
FJ KS ~ 18F > 0NH NJ
8 C2 7 H34 F' FNI0 4 Si:571.69 C2 lH 22 F'BFN 6 02 : 427.45 'OF -Teoc-2- Larotrectinib 18 F -2- Larotrectinib
(7) Labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Piv-2-Larotrectinib based on the following reaction formula: F F H /0 0
Hi 18F CN
H 0 <
18 H C39H44FINGO 7:854.72 C 26H30F FINO03:511.56 I(111-SPIAd -Piv-2- Larotrectinib I -Piv-2-Larotrectinib
F F 0
NN 0 N-N 0H 18 18Fx0 - F
0 0 18 C 26H 30 F'$F1N 603:511.56 C 21 H 22F F1N0 2:427.45 (8) 1 -Piv-2-Larotrectinib 18 F -2- Larotrectinib labeled
product [ 18 F] -2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Ac-2-Larotrectinib based on the following reaction formula:
F F 0 0
8 0 N F -N O1AH
H 18 C 36H 38FIN 60: 812.64 C23H 24F FINS0 3:469.48 I(111-SPIAd -Ac -2-Larotrectinib 18 F -Ac-2-Larotrectinib
F F 0
N- OAC N -N OH 18 18 F C 3 F
HN-N6 NJ N
18 C23 H 24FIOF1N 60 3:469.48 C 23H 24F F1N60 2:427.45 18 1F- Ac-2-Larotrectinib F- 2-Larotrectinib
(9) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Tf-2-Larotrectinib based on the following reaction formula:
F F 0 0
/0 // H- N- N~ OA CJN(5 N5 %N
00
H 18 C 36H 35F4 1N07: 866.61 C23 H2lF 4 FINO0 3:523.45 I(111-SPIAd-MT--2-Larotrectinib 18 F-Tf-2-Larotrectlnlb
F F 0
18 F aN N~
HN6 (5 OAN 18 F // $JN -N O
NN 18 18 C 23 H2lF 4 FIN 603 :523.45 C23 H 24F F1N60 2:427.45 18 1F- Tf-2-Larotrectinib F- 2-Larotrectinib
(10) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-CAc-2-Larotrectinib based on the following reaction formula:
F F 0 0
/ oo - 6 CH C /- - NCHC
F8 FC 00
H3 3 CIF N0: 708 C 23H 2CF IN603:03.45 I(IQSFd-CAc-2-Larotrectinib 18 F ~-2-Larotrectinib
F F
0 ~ . 0
1 18 CHC 18FI F
aN 2 HI
H~ONJ N6~ HN
1 H H2 C H 36CN6 F1 03 6 81.5 2C23 4FFHS 2 2 F FN 4 6538 8 'OF -C -S-La o Cr c -2-artrctni F- DCotr c-2-artrctn
F F 0
HO
18 HC^0FN 788.2 C23H 22C1 2F FN 603 :538.37 C 2H FFN0:4.5 8 18 I I-DC A - Ara -Ltrectinib F D c-2-Larotrectinib
(1)aeepoucF 8 ]2LrteciiipeaeFmhlbedecso
I(I)SP~-oc2Lrorcinbaeonhfllwnrecinfrua
147H
F F 0 0 0 ~ ~ N OA__ ~ N N\ O 8 HNI F 0H 0N HNW N HN_-N 0 0
H 18 C 36H 38 FN 60:828.64 C23H 24F FINS0 4:485.48 18 I(11)-SPIAd -Mo-2- Larotrectinib F -Moc-2-Larotrectinib
F F 0
-N0AON-N N' O H 18 NB FN P HN_ ,6 N HN N6
8 C 23H 2 4FI FIN 604 :485.48 C2 3H 24FIOF1Nr 60 2:427.45 '- Moc-2-Larotrectinib 'OF- 2-Larotrectinib
(13) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Eoc-2-Larotrectinib based on the following reaction formula:
F F 0 0
0 N N~ 0_____ 5 NN O
H C37H 40FN 60 8: 842.66 18 C24H 26F FIN 6O 4:499.51 I(111-SPIAd -Eoc-2- Larotrectinib 'OF -Eoc-2-Larotrectinib
F F 0
0 / - N 0_ N -N OH NO 18FNN
18 18 C 24H 26 F F1N 604:499.51 C2 3H 24F FIN602 :427.45 1 'OF- Eoc-2-Larotrectinib OF-2- Laratrectinib
(14) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Boc-2-Larotrectinib based on the following reaction formula:
F F 0 0
18 H C18FNO:707 2 H 0 I~ 4 575
0 F, F
aN N N-
, 00 1 8 H CH30F F IN 60:70. C23F FN 60:27.5 18 I(F-Bo-2Pd- a-Larotrectinib F- -2-Larotrectin b
F F 00
1,; Nd O /N 5_ - N OH
0 0 8 H C3 H3 ,F C1FFfl0,:5 45 9 C3H 2 3 F FIN 6 2 4 62.4 1OF- B - ~- Trc-Lrtrtrctlnlb 'OF-TLro2Lrtrectnb
F F
N _N 18F NCI NNA o 0 3C 31F H 3 F IN 60S:602.84 C 2 H2 F N 4 6 02 .84 18 I F PId-Troc-2-Larotrectinib OF o-2-Larotrectinib
(1)aeepoutF 8 ]2Lrtetniipeaefothlbldrcro I(II-SI~-To-2Laotecinbasdothfoloigraciofomua
ox /; N - 0A N -149
F F
o-N - 0#0
H~~Q N H NrI 18F ~§CI
18 H C37H 31 C13 F1N 6 08 :945.99 C 24H23C1 3F F1NO0 4:602.84 I(111-SPIAd -Troc-2-Larotrectlnlb 'OF-Troc-2-Larotrnctinib
F F 0 / /0OH N' 18 18 F F
N ~N ~
18 18 C 24H 23C1 3F F1N 604:602.84 C 2,HF FIN 60 2 :427.45 18 F- Troc-2-Larotrectinib 'OF- 2-Larotrectinib
(17) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-PMB-2-Larotrectinib based on the following reaction formula:
F Na OMe O F\, OMe
0H 0 0 0 8 0~~~ 2 8 H C 42H 44F1N 60 7:890.75 C 29H30F' F1NI0 3:547.60 I(111-SPAd -PMB-2-Lrtcii I(I1)SPIAd -MB-2-Larotrectinib
F F
18 F 18FH
8 18 C 29 H, 0 F' FIN 6 0 3 :547.60 C 23H24F FIN 60 2 :427.45 I(111-SPIAd -PMB-2-Larotrectinib 'OF- 2-Larotrectinib
(18) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-MOM-2-Larotrectinib based on the following reaction formula:
F F
00 oj N-N r~NOO OMOM
Hi4 00 HN_
18 H C36 1140 F1N 6 0 7 :814.65 C 23H 26F FIN 603:471.50 I(111-SPIAd -MOM-2-Larotrectinib 18 F-MOM- 2-Larotrectinib
F F
~'~N OMOM ~ _ N OH aNK
8 C,,H, 6 F' F1NI0 3 :471.50 C 23H 24 F'OF10 2:427.45 18 F- MOM-2-Larotrectinib 'OF- 2-Larotrectinib
(19) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-MEM-2-Larotrectinib based on the following reaction formula:
F F
H 0 O N NN N ~
HN6b OMEM 18 F o 5 .
N3 N- OMEM
N6
H C 3 sH 44 F1N6 0 8 :858.71 C 25H 30F'gF1N 60 4:515.55 18 I(111-SPIAd -MEM-2-Larotrectinib F-MEM-2- Larotroctinib
F F
NN OMEM / _ N N OH 18 F F
C 2sH 30FIOF1N 60 4:515.55 C 23 H 24F'OF1N 60 2:427.45 18 'OF- MEM-2-Larotrectinib F- 2-Larotrectinib
(20) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-THP-2-Larotrectinib based on the following reaction formula:
F F -0 0 N-N' 0 0
H,~ O N N ____18F
0 0 18 H C39 H44FLN 60 7 Si:854.72 C 26HSOF FINSO 3:511.56 18 I(11)-SPIAd -THP-2-Larotrectinib F-THP- 2-Larotroctinib
F F
18F 18F ~ ~ O
KliN N6iN N6 00 1 18 C2 6H 30 F F1NS0 3 :511.56 C 23H 24F FIN60 2:427.45 18 18 F-THP-2- Larotrectinib F- 2-Larotrectinib
(21) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-EE-2-Larotrectinib based on the following reaction formula:
F F
0 0 0
18 H I F 0 1N HN6 N H~
18 H C 3gH 44 F1N 60 7 :842.71 C25H30F F1N 603 :499.55 18 I(111-SPIAd -EE-2-Larotrectinib F-EE- 2-Larotrectinib
F F
N OH
18FE--artecii 18F-Lrtocii
N 152
(22) labeled product [ 18 F]-2-Larotrectinib is prepared from the labeled precursor
I(III)-SPIAd-Als-2-Larotrectinib based on the following reaction formula:
F F 00
aN>
18 H C 371E 4 0FIN 6 0 8 S:874.72 C24H26 F FP1 6 04 S:531.57 I(111-SPIAd -As-2-Larotrectinib I(11)-SPIAd -As-2-Larotrectinib
F F 0
- N /- N OH
N HN-(N N N
0 0 18 1 C2 4H2 6F F][N 604 S:531.57 C 23 H 24F OF1NS0 2 :427.45 18 I(111-SPIAd -As-2-Larotrectinib F-2- Larotrectinib
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