WO2020119205A1 - 一种放射性氟标记Larotrectinib化合物及其制备方法 - Google Patents

一种放射性氟标记Larotrectinib化合物及其制备方法 Download PDF

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WO2020119205A1
WO2020119205A1 PCT/CN2019/106690 CN2019106690W WO2020119205A1 WO 2020119205 A1 WO2020119205 A1 WO 2020119205A1 CN 2019106690 W CN2019106690 W CN 2019106690W WO 2020119205 A1 WO2020119205 A1 WO 2020119205A1
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larotrectinib
spiad
iii
follows
preparation
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PCT/CN2019/106690
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French (fr)
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黄钢
李斌
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上海健康医学院
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    • 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

Definitions

  • the present invention relates to the field of chemical drug synthesis, especially in vivo imaging agents of Trk receptor subtypes in refractory solid tumors, and specifically relates to radioactive fluorine based on a novel inhibitor Larotrectinib against tyrosine receptor kinase (TRK) Compound 18 F-Larotrectinib and its 18 F-Larotrectinib analog, more particularly relates to a method of preparing Larotrectinib and its analog radioactive fluorine-18 labeled compound 18 F-Larotrectinib and its 18 F-Larotrectinib analog.
  • TRK tyrosine receptor kinase
  • Larotrectinib was developed by Loxo Oncology as a broad-spectrum tumor drug for all tumor patients expressing tropomyosin receptor kinase (TRK). This TRK small molecule inhibitor is very useful for TRK Strong selectivity, by inhibiting the TRK signaling pathway, larotrectinib can inhibit tumor growth.
  • Larotrectinib is a powerful oral TRK inhibitor with consistent and long-lasting antitumor activity in TRK fusion tumors. It is suitable for a wide range of patient ages and tumor types.
  • Larotrectinib is expected to be the first therapeutic drug developed and approved in adults and children at the same time, 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:
  • positron-emitting radiopharmaceuticals 18F-deoxyglucose (18F-FDG) is usually used to indirectly evaluate the therapeutic effect of drugs on tumors and related diseases, and positron-emitting radioactivity
  • the drug 18F-deoxyglucose (18F-FDG) also has high FDG absorption in non-tumor tissues and inflammatory cell components, which may cause false positive results of tumor diagnosis due to the presence of inflammation when FDG is used in tumor imaging.
  • PET Pulsitron Emission Tomography
  • TRK tropomyosin receptor kinase
  • the purpose of the present invention is to provide a [ 18 F]-labeled Larotrectinib compound and its preparation method in order to overcome the above-mentioned defects in the prior art.
  • a [ 18 F]-labeled Larotrectinib compound which is characterized by comprising an 18 F-Larotrectinib compound having the following structural formula and its analogues:
  • Step one hydroxyl protection: protection of the active hydroxyl functional group of the precursor of I-Larotrectinib analog (I-Larotrectinib);
  • Step 2 Preparation of labeling precursor: I-Larotrectinib analog precursor (I-Larotrectinib) Iodine is activated to prepare trifluoroacetic acid iodinated Larotrectinib analog, which is then reacted with auxiliary acid substituted by adamantane to prepare labeling precursor: spiro ring Larotrectinib analogs protected by iodine (III) hydroxy groups;
  • Step 3 Preparation of fluorine-18 labeling product: the reaction of labeling precursor with fluorine-18 radioactive source to prepare the synthesis of hydroxyl-protected 18F-Larotrectinib and the synthesis of 18F-Larotrectinib analogue, and then deprotection to obtain 18F-Larotrectinib and 18F -Larotrectinib analogues.
  • the precursor of the iodinated Larotrectinib analog in step one includes the following structural formula:
  • R1 and R2 each independently represent a phenyl substituent, and R1 and R2 are each independently selected from H, halogen, hydroxy, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Group consisting of C3-10 cycloalkyl, C6-10 aryl, C4-10 heterocycloalkyl, and C6-10 heteroaryl; R1, R2 each independently form a group with R3;
  • R3 specifically represents H; the protection of the active hydroxyl functional group means that R3 is substituted by the following functional groups through esterification or etherification to protect the active hydroxyl group.
  • the substituted functional groups include trimethylsiloxy Ether (TMS), tert-butyl dimethyl siloxane ether (TBDMS), triethyl silicone ether (TES), tert-butyl diphenyl siloxane ether (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-methoxyethoxymethyl ether (MEM), methylthiomethyl ether (MTM), benzyloxymethyl ether (BOM), p-methoxybenzyl ether (P
  • the preparation of the iodo-Larotrectinib analog of trifluoroacetic acid in step two is to prepare the active hydroxyl-protected i-Larotrectinib analog precursor (I-Larotrectinib) prepared in step one, with trifluoroacetic acid or trifluoroacetic anhydride, Organic solvent and oxidant react to make I activated by trifluoroacetate;
  • the organic solvent includes one or more of chloroform, dichloromethane, acetonitrile, acetone, tert-butanol peroxide;
  • the oxidant includes urea-hydrogen peroxide complex, Oxone, 2,2,6,6-tetramethylpiperidine-oxide or mCPBA.
  • the auxiliary acid substituted by adamantane in step 2 is SPIAd.
  • the reaction conditions of SPIAd and trifluoroacetic acid iodo Larotrectinib analog are: SPIAd and one or more of sodium carbonate solution, MeCN, NaHCO3 and acetone at 0°C Mix, and control the pH value of the mixed solution to be 8 to 10, and continuously stir the reaction with trifluoroacetic acid iodo Larotrectinib analog at 0°C for 1 to 10 hours to obtain the labeled precursor.
  • the fluorine-18 radioactive source described in Step 3 is obtained by the following method:
  • [ 18 F]fluorinated target water was produced by 1 8 O(p,n) 18 F nuclear reaction, using GE PETTrace cyclotron, and [ 18 F]fluorine was converted by nitrogen pressure
  • the compound target water is delivered to a sterile lead-protected hot cell with 18 O-enriched water; the [ 18 F]fluoride target water produced by this method is usually used Milli-Q (Millibe Ultra Pure Water instrument) ultra-purified water is further diluted to 1-3mCi/ml [ 18 F] fluoride target water liquid;
  • the substitution reaction of the labeling precursor described in step three with the fluorine-18 radioactive source take a V-shaped vial containing dried [ 18 F]fluoride organic salt or inorganic salt, add solvent to re-dissolve, and then add the labeling precursor to proceed The reaction yielded a crude reaction solution of [ 18 F]-Larotrectinib undeprotected label.
  • step three The deprotection described in step three is achieved by the following method: using no or adding a certain amount of organic base or inorganic base or organic acid or inorganic acid to the crude reaction liquid of [ 18 F]-Larotrectinib undeprotected marker, The hydroxyl protecting group was removed under heating to obtain a crude reaction solution of [ 18 F]-Larotrectinib label.
  • the crude reaction liquid of the [ 18 F]-Larotrectinib marker also needs to be separated and purified by the following method:
  • the crude reaction liquid of the [ 18 F]-Larotrectinib marker is prepared by using semi-preparative HPLC or Waters Sep-Pak C-18
  • the small column was purified and rinsed with a solvent into a sterile vacuum bottle, and dried with nitrogen at 60°C for 20 minutes, and reconstituted with saline, which contained 100ul, 25% vitamin C in water, 100ul, 20% Tween 80 ethanol Solution, that is, [ 18 F]-Larotrectinib marker injection, the [ 18 F]-Larotrectinib marker injection was analyzed and identified by the following methods:
  • radioactive HPLC 60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C 18 , 250 ⁇ 4.6mm, 5 ⁇ m, UV at 254nm; CH 3 CN/0.1M NH4 ⁇ HCO 2 (aq)( v/v, 7/3), flow rate 1.0 mL/min) and radioactive TLC (EtOAc+0 ⁇ 5% EtOH) to determine product identification and purity (radiochemical purity and chemical purity).
  • the radiochemical purity of the product is >90-99%.
  • the chemical purity of the product is >90-99%.
  • the radiochemical yield was determined as the percentage of radioactivity separated from the final product as a percentage of the radioactivity separated from the V-vial of [ 18 F]Et 4 NHCO 3 solution diluted with the addition of the labeled precursor to DMF, and without decay correction.
  • the radiochemical yield is 20-45.3 (without attenuation correction), the radiochemical purity is greater than 99%, and the specific activity is 2.56-18Ci/ ⁇ mol).
  • the present invention has the following beneficial technical effects:
  • the present invention provides a fluorine-18-labeled 18 F-Larotrectinib compound and its analogs, and provides a method for preparing a fluorine-18-labeled Larotrectinib compound and its analogs, that is, using a trivalent iodine substitution method
  • Fluorine-18-labeled 18 F-Larotrcetinib has fast reaction speed, relatively mild conditions, simple operation, short reaction time, and simple post-treatment. It can prepare carrier-free radiolabeled compounds with high radiochemical purity.
  • the present invention provides a fluorine-18-labeled 18 F-Larotrectinib compound and its analogues, which has the property of emitting positrons, and visually displays the Larotrectinib compound and its analogues by means of PET-CT positron emission tomography In vivo, as well as the distribution of tumors, and provides a new imaging agent for early diagnosis of tumors.
  • R3 specifically represents H.
  • Step 1 Key intermediate 4 and its synthesis
  • Step 2 Key intermediate 8 and its synthesis
  • Step 1 Key intermediate 4 and its synthesis
  • the solid was dissolved in glacial acetic acid (50mL), concentrated hydrochloric acid (36%, 5mL), the mixture was heated to reflux for 4 hours, the acetic acid was removed under reduced pressure, the residue was extracted with ethyl acetate (300mL), washed with brine 3 times, 100mL each time, organic The phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the target product (26.89 g, 56%) as a yellow solid, MP146°.
  • step 1c (19.1g, 0.05mol) in 50mL of methanol.
  • the liquid is added dropwise to a saturated solution of methanol-ammonia, keeping the internal temperature around 0 degrees. After the dropwise addition was completed, the reaction solution continued to react at zero degrees for 16 hours.
  • the reaction solution was detected by TLC to step 1c, when the esterified product basically disappeared, the reaction was stopped, the solvent was removed under reduced pressure, and the oily substance obtained was used directly in the next step.
  • Examples 1 to 42 are the first step of hydroxy protection, preparation of I hydroxy protected Larotrectinib compound
  • the preparation method is the same as that in Example 1.
  • the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Bz-5-Larotrectinib with a yield of 88% (70.4 mmol, 45.1 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 3, and the compound I-5-Larotrectinib is used as the raw material to obtain the product I-Piv-5-Larotrectinib as a white solid with a yield of 85% (70.4 mmol, 42.2 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 5, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Ac-5-Larotrectinib.
  • the yield is 96.5% (77.2 mmol, 44.7 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 7, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Tf-5-Larotrectinib with a yield of 94% (75.2 mmol, 59.4 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 9, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-DCAc-5-Larotrectinib in a yield of 91% (73 mmol, 47 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 11, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Moc-5-Larotrectinib, with a yield of 91% (73 mmol, 47 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 13, and the compound I-5-Larotrectinib is used as the raw material to obtain the product I-Eoc-5-Larotrectinib as a white solid in a yield of 94% (75 mmol, 75 g).
  • the route is as follows:
  • the preparation method is the same as that in Example 15, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Boc-5-Larotrectinib with a yield of 94% (75 mmol, 47 g).
  • the preparation method is the same as that in Example 17, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Boc-5-Larotrectinib with a yield of 91% (72.8 mmol, 51 g).
  • the preparation method is the same as that in Example 19, and the compound I-5-Larotrectinib is used as the raw material to obtain the product I-Teoc-5-Larotrectinib as a white solid in a yield of 83% (66.4 mmol, 45 g).
  • the preparation method is the same as that in Example 21, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-TBS-5-Larotrectinib with a yield of 86% (68.8 mmol, 45 g).
  • the preparation method is the same as that in Example 23, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-TIPS-5-Larotrectinib, with a yield of 88% (70.4 mmol, 49 g).
  • the preparation method is the same as that in Example 25, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-TBDPS-5-Larotrectinib, with a yield of 86% (68.8 mmol, 53 g).
  • the preparation method was the same as in Example 27, and the compound I-5-Larotrectinib was used as the raw material to obtain the product as a white solid I-PMB-5-Larotrectinib in a yield of 83% (66.4 mmol, 43.6 g).
  • the preparation method is the same as that in Example 29, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-MOM-5-Larotrectinib in a yield of 74% (59 mmol, 34 g).
  • the preparation method is the same as that in Example 30, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-MEM-5-Larotrectinib, with a yield of 76% (60.8 mmol, 38 g).
  • the preparation method is the same as that in Example 33, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-SEM-5-Larotrectinib with a yield of 86% (68.8 mmol, 46 g).
  • the preparation method is the same as that in Example 35, and the compound I-5-Larotrectinib is used as the raw material to obtain the product I-THP-5-Larotrectinib as a white solid with a yield of 98% (78.4 mmol, 48 g).
  • the preparation method is the same as that in Example 37, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-EE-5-Larotrectinib in a yield of 85% (68 mmol, 41 g).
  • the preparation method is the same as that in Example 39, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-Als-5-Larotrectinib in a yield of 86% (68.8 mmol, 44 g).
  • the preparation method is the same as that in Example 41, and the compound I-5-Larotrectinib is used as the raw material to obtain the product as a white solid I-PMP-5-Larotrectinib with a yield of 81% (64.8 mmol, 43.6 g).
  • I(III)-SPIAd-Bz-5-Larotrectinib was prepared in a similar manner to Example 43 to obtain the product I(III)-SPIAd-Bz-5-Larotrectinib as a white solid in a yield of 19% (18 mmol, 18 mg).
  • reaction mixture was heated to 40°C for reaction 1- After 6 hours, TLC detected that the raw material I-Piv-2-Larotrectinib had been reacted, then diluted with 2.5 mL of water, extracted three times with DCM, 5 mL each time, combined organic phases, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was silica gel column Analysis (elution with 0-10% methanol in ethyl acetate) gave intermediate I-Piv-TfAc-2-Larotrectinib as a white solid (143.91 mg, 68% yield).
  • the filter cake is washed twice with 5mL each time. The water needs to be drained for each wash.
  • the filter cake is reused Wash with diethyl ether (10mL) once and dry under high vacuum to obtain the labeling precursor I(III)-SPIAd-Piv-2-Larotrectinib off-white solid (113.33mg, 78%, total yield in 2 steps 53%), mp100 degrees ( break down).
  • I(III)-SPIAd-Piv-5-Larotrectinib was prepared in a similar manner to Example 45 to obtain the product as a white solid I(III)-SPIAd-Piv-5-Larotrectinib, yield 78% (113 mg, total yield in 2 steps 53) %).
  • TLC detected the starting material I-Ac-2-Larotrectinib.
  • the reaction was completed, the reaction was transferred into 3mL of ice water and diluted, extracted three times with DCM, 5mL each time, combined organic phase, common salt Wash 3 times with 2 mL each time, dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under reduced pressure, and the residue is silica gel column chromatography (eluted with 0-10% methanol in ethyl acetate) to obtain intermediate I-Ac- TfAc-2-Larotrectinib light yellow solid (114.68 mg, 0.143 mmol, 64.8% yield).
  • I(III)-SPIAd-Ac-5-Larotrectinib was prepared in a similar manner to Example 47 to obtain the product I(III)-SPIAd-Ac-5-Larotrectinib as a white solid in 46% yield (138 mg).
  • TLC detected the raw material I-Tf-2-Larotrectinib.
  • the reaction was completed, the reaction was transferred to 3mL of ice water and diluted, extracted three times with DCM, each 5mL, combined organic phase, common salt Wash with water 3 times, 2mL each time, dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under reduced pressure, and the residue is silica gel column chromatography (eluted with 0-10% methanol in ethyl acetate) to obtain intermediate I-Tf- TfAc-2-Larotrectinib light yellow solid (117.46 mg, 0.137 mmol, 62.2% yield).
  • the reaction flask was washed with dichloromethane three times, 0.12 mL each time.
  • the washing liquid rinsed the insoluble matter and collected a yellow liquid of dichloromethane.
  • I(III)-SPIAd-Tf-5-Larotrectinib was prepared in a similar manner as in Example 49 to obtain the product I(III)-SPIAd-Tf-5-Larotrectinib as a white solid in 46% yield (54 mg).
  • the reaction flask was washed with dichloromethane three times, 0.12 mL each time.
  • the washing liquid rinsed the insoluble matter and collected a yellow liquid of dichloromethane.
  • I(III)-SPIAd-CAc-5-Larotrectinib was prepared in a similar manner to Example 51 to obtain the product I(III)-SPIAd-CAc-5-Larotrectinib as a white solid in 46% yield (27 mg).
  • I(III)-SPIAd-DCAc-5-Larotrectinib was prepared in a similar manner to Example 53 to obtain the product as a white solid I(III)-SPIAd-DCAc-5-Larotrectinib (43mg, yield 47%, total yield in 2 steps 46.8 %).
  • the reaction was transferred into 3 mL of water for dilution, and extracted three times with DCM, each with 5 mL. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (0-40% ethyl acetate-petroleum ether solution elution) to obtain the labeling precursor I(III)-SPIAd-Moc-2-Larotrectinib as a white solid (38.91 mg, yield 31.3%).
  • I(III)-SPIAd-Moc-5-Larotrectinib was prepared in a similar manner to Example 55 to obtain the product I(III)-SPIAd-Moc-5-Larotrectinib as a white solid in a yield of 31% (39 mg).
  • reaction was followed by TLC until the conversion of the raw materials was completed.
  • the reaction was transferred into 3mL of water for dilution, and extracted with DCM three times, 5mL each time.
  • the organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure. Analysis (0-40% ethyl acetate-petroleum ether solution elution) to obtain the labeling precursor I(III)-SPIAd-Eoc-2-Larotrectinib as a white solid (33.57 mg, yield 33.2%).
  • I(III)-SPIAd-Eoc-5-Larotrectinib was prepared in a similar manner to Example 57 to obtain the product I(III)-SPIAd-Eoc-5-Larotrectinib as a white solid in 33% yield (34 mg).
  • I(III)-SPIAd-Boc-5-Larotrectinib was prepared in a similar manner to Example 59 to obtain the product I(III)-SPIAd-Boc-5-Larotrectinib as a white solid in a yield of 40% (49 mg).
  • the reaction was transferred into 3 mL of water for dilution, and extracted three times with DCM, each with 5 mL.
  • the organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the residue was subjected to silica gel column chromatography ( 0-40% ethyl acetate-petroleum ether solution elution) to obtain the labeling precursor I(III)-SPIAd-Troc-2-Larotrectinib as a white solid (53.92 mg, yield 38%).
  • I(III)-SPIAd-Troc-5-Larotrectinib was prepared in a similar manner to Example 61 to obtain the product I(III)-SPIAd-Troc-5-Larotrectinib as a white solid in a yield of 38% (53 mg).
  • TLC detected the raw material I-Teoc-2-Larotrectinib.
  • the reaction was completed, the reaction was transferred to 3mL of ice water and diluted, extracted three times with DCM, each 5mL, combined organic phase, common salt Wash with water 3 times, 2mL each time, dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under reduced pressure, and the residue is silica gel column chromatography (eluted with 0-10% methanol in ethyl acetate) to obtain intermediate I-teoc- TfAc-2-Larotrectinib light yellow solid (153.96 mg, 0.173 mmol, 78.4% yield).
  • the filter cake is washed twice with 5mL each time. The water needs to be drained for each wash.
  • the filter cake is reused Wash with diethyl ether (10mL) once and dry under high vacuum to obtain the labeling precursor I(III)-SPIAd-Teoc-2-Larotrectinib off-white solid (121.31mg, 78%, 2 steps total yield 61.1%), mp115 degrees (break down).
  • I(III)-SPIAd-Teoc-5-Larotrectinib was prepared in a similar manner to Example 63 to obtain the product as a white solid I(III)-SPIAd-Teoc-5-Larotrectinib (121 mg, 78%, 2 steps total yield 61%) .
  • I(III)-SPIAd-TBS-5-Larotrectinib was prepared in a similar manner to Example 65 to obtain the product I(III)-SPIAd-TBS-5-Larotrectinib (38 mg, 30%) as a white solid.
  • I(III)-SPIAd-TBS-5-Larotrectinib was prepared in a similar manner to Example 67 to give the product I(III)-SPIAd-TBS-5-Larotrectinib (38 mg, 30%) as a white solid.
  • I(III)-SPIAd-TBS-5-Larotrectinib was prepared in a similar manner to Example 69 to obtain the product I(III)-SPIAd-TBS-5-Larotrectinib (53 mg, 35%) as a white solid.
  • I(III)-SPIAd-TIPS-5-Larotrectinib was prepared in a similar manner to Example 71 to obtain the product as a white solid I(III)-SPIAd-TIPS-5-Larotrectinib (42 mg, total yield in 2 steps 42%).
  • I(III)-SPIAd-PMB-5-Larotrectinib was prepared in a similar manner to Example 73 to obtain the product I(III)-SPIAd-PMB-5-Larotrectinib as a white solid (45 mg, 34%).
  • I(III)-SPIAd-MOM-5-Larotrectinib was prepared in a similar manner to Example 75 to obtain the product as a white solid I(III)-SPIAd-MOM-5-Larotrectinib (38 mg, total yield in 2 steps 43%).
  • I(III)-SPIAd-MEM-5-Larotrectinib was prepared in a similar manner to Example 77 to obtain the product as a white solid I(III)-SPIAd-MEM-5-Larotrectinib (30 mg, 2 steps total yield 32%).
  • I(III)-SPIAd-SEM-5-Larotrectinib was prepared in a similar manner to Example 79 to obtain the product as a white solid I(III)-SPIAd-SEM-5-Larotrectinib (20 mg, total yield in 2 steps 21%).
  • I(III)-SPIAd-THP-5-Larotrectinib was prepared in a similar manner to Example 81 to give the product I(III)-SPIAd-THP-5-Larotrectinib (27 mg, 28%) as a white solid.
  • I(III)-SPIAd-EE-5-Larotrectinib was prepared in a similar manner to Example 83 to obtain the product as a white solid I(III)-SPIAd-EE-5-Larotrectinib (40 mg, total yield in 43 steps).
  • reaction solution was transferred to a reaction flask containing 5mL for dilution, and extracted three times with dichloromethane, 5mL each time, the organic phases were combined and washed with saturated brine, Anhydrous magnesium sulfate was dried, 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) to obtain the labeled precursor I(III)-SPIAd-Als-2-Larotrectinib yellow Color solid (25.72mg, yield 21%).
  • I(III)-SPIAd-Als-5-Larotrectinib was prepared in a similar manner to Example 85 to obtain the product I(III)-SPIAd-Als-5-Larotrectinib (26 mg, 21%) as a white solid.
  • I(III)-SPIAd-PMP-5-Larotrectinib was prepared in a similar manner to Example 87 to obtain the product as a white solid I(III)-SPIAd-PMP-5-Larotrectinib (43 mg, 33%).
  • Step 1 Preparation of [ 18 F]fluoride target water: [ 18 F]fluoride target water is produced by 1 8 O(p,n) 18 F nuclear reaction. A GE PETTrace cyclotron was used (40 ⁇ A beam for 2 minutes can produce about 150 mCi[ 18 F]fluoride target water). Nitrogen pressure by [18 F] fluoride target water is delivered to the lead 18 O- sterile chamber thermal protection enriched water produced by this method of [18 F] fluoride target water prior to use in research, usually Milli-Q (Millibo Ultra-Pure Water Instrument) ultra-purified water is further diluted to 1-3mCi/ml [ 18 F] fluoride target water liquid.
  • Milli-Q Milllibo Ultra-Pure Water Instrument
  • QMA anion exchange solid phase extraction cartridge enriches [ 18 F]fluoride: an aliquot of target water containing an appropriate amount of [ 18 F]fluoride, under nitrogen flow, slowly passes through the anions
  • An exchange solid phase extraction cartridge (QMA) which is preliminarily pre-washed by using NaHCO 3(aq) (8.4%, 1 mL) and water (20 mL until the pH indicator is neutral)
  • [ 18 F]fluoride is enriched on QMA anion exchange solid phase extraction cartridge (QMA), and 18 O and other impurities are separated and eluted to obtain [ 18 F]fluoride QMA anion exchange solid phase [ 18 F]fluorine source of extraction cartridge (QMA).
  • Step 3 Elute the [ 18 F]fluoride enriched on the QMA anion exchange solid phase extraction cartridge (QMA) to obtain the [ 18 F]fluoride quaternary ammonium salt or inorganic salt solution: use an organic or inorganic base (for example, certain Amount of tetraethylammonium bicarbonate, for example 8mg, dissolved in acetonitrile and water (1mL, v/v 7:3) or acetonitrile (1mL) or methanol (1mL) or ethanol (1mL), rinse and enrich [ 18 F]fluoride on QMA anion exchange solid phase extraction cartridge (QMA), elute [ 18 F]fluoride into a V-shaped vial sealed with a Teflon liner septum to obtain [ 18 F]fluoride Acetonitrile aqueous solution or acetonitrile or methanol solution of organic salt or inorganic salt of compound.
  • an organic or inorganic base for example, certain Amount of te
  • Step 4 Preparation of dry [ 18 F]fluoride quaternary ammonium salt or inorganic salt: Teflon liner membrane containing [ 18 F]fluoride organic salt or inorganic salt in acetonitrile aqueous solution or acetonitrile or methanol or ethanol solution
  • the sealed V-shaped vial was heated to 95-110°C, while nitrogen gas was dried through a P 2 O 5 -Drierite TM column, the V-shaped vial was purged, and then the exhaust gas was discharged through the vented vial. When no liquid was visible in the vial, remove it from the hot bath, add anhydrous acetonitrile (1 mL), and resume heating until dry. Repeat this step three more times.
  • [ 18 F]fluoride organic salt or inorganic salt such as [ 18 F]KF/K 2 CO 3 /K 2.2.2 , [ 18 F]KF/ K 2 C 2 O 4 /K 2.2.2 , [ 18 F]KF/KOTf, [ 18 F]Et 4 NF, [ 18 F]Et 4 NHCO 3 , [ 18 F]Et 4 NOMs, [ 18 F]Et 4 NOTf, its radioactive [ 18 F]fluoride recovery rate varies according to the elution process used.
  • [ 18 F]fluoride organic salt or inorganic salt such as [ 18 F]KF/K 2 CO 3 /K 2.2.2 , [ 18 F]KF/ K 2 C 2 O 4 /K 2.2.2 , [ 18 F]KF/KOTf, [ 18 F]Et 4 NF, [ 18 F]Et 4 NHCO 3 , [ 18 F]Et 4 NOMs, [ 18 F]Et 4 NOTf, its radioactive [ 18 F]fluoride
  • Step 5 Construction of [ 18 F]-Larotrectinib marker reaction system: take a V-shaped vial containing dried [ 18 F]fluoride organic salt or inorganic salt (activator measurement (t 0 ) activity), add The required solvent (such as DMF) is re-dissolved, and then the labeling precursor is added to react under certain conditions to obtain a crude reaction solution of [ 18 F]-Larotrectinib undeprotected label.
  • Step 6 [ 18 F]-Larotrectinib unprotected marker deprotection: adopt no or add a certain amount of organic base or inorganic base or organic acid or inorganic acid to the reaction solution, remove the hydroxyl protection under heating conditions Base to obtain the crude reaction solution of [ 18 F]-Larotrectinib marker.
  • Step 7 Separation and purification of [ 18 F]-Larotrectinib marker: Semi-preparative HPLC or Waters Sep-Pak C-18 cartridge purification was used to prepare high-purity [ 18 F]-Larotrectinib labeled product, which was rinsed with a solvent into sterile Vacuum bottle, blow dry with nitrogen at 60 degrees for 20 minutes, reconstitute with brine, which contains 100ul, 25% vitamin C in water, 100ul, 20% Tween 80 in ethanol to obtain [18F]-Larotrectinib marker Injection.
  • Step 8 Analysis and identification of [ 18 F]-Larotrectinib marker: by radioactive HPLC (60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C 18 , 250 ⁇ 4.6mm, 5 ⁇ m, UV at 254nm ; CH 3 CN/0.1M NH4 ⁇ HCO 2 (aq) (v/v, 7/3), flow rate 1.0mL/min) and radioactive TLC (EtOAc+0 ⁇ 5% EtOH) to determine product identification and purity (radiochemistry Purity and chemical purity).
  • the radiochemical purity of the product is >90-99%.
  • the chemical purity of the product is >90-99%.
  • the radiochemical yield was determined as the percentage of radioactivity separated from the final product as a percentage of the radioactivity separated from the V-vial of [ 18 F]Et 4 NHCO 3 solution diluted with the addition of the labeled precursor to DMF, and without decay correction.
  • the radiochemical yield is 20-45.3 (without attenuation correction), the radiochemical purity is greater than 99%, and the specific activity is 2.56-18Ci/ ⁇ mol).
  • [ 18 F]fluoride organic salt or inorganic salt such as [ 18 F]KF/K 2 CO 3 /K 2.2.2 , [ 18 F]KF/ K 2 C 2 O 4 /K 2.2.2 , [ 18 F]KF/KOTf, [ 18 F]Et 4 NF, [ 18 F]Et 4 NHCO 3 , [ 18 F]Et 4 NOMs, [ 18 F]Et 4 NOTf, its radioactive [ 18 F]fluoride recovery rate varies according to the elution process used.
  • [ 18 F]fluoride organic salt or inorganic salt such as [ 18 F]KF/K 2 CO 3 /K 2.2.2 , [ 18 F]KF/ K 2 C 2 O 4 /K 2.2.2 , [ 18 F]KF/KOTf, [ 18 F]Et 4 NF, [ 18 F]Et 4 NHCO 3 , [ 18 F]Et 4 NOMs, [ 18 F]Et 4 NOTf, its radioactive [ 18 F]fluoride
  • Test data such as (Table 1, the effect of different eluents and organic or inorganic bases on the elution efficiency of [ 18 F] fluoride) and (Table 2, the loading of different organic or inorganic bases on [ 18 F] fluoride wash For the effect of desorption efficiency, use acetonitrile as the elution solvent).
  • a 400 uL sample was separated from the above DMF solution and added to a V-shaped reaction flask ([ 18 F]Et 4 NOMs) added with a labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib white solid (4.0 mg) Usually 1.35mCi).
  • the mixture was heated to 120 degrees for 20 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction sample (1-2uL) was detected to have [ 18 F] -Bz2--Larotrectinib labeled product.
  • the samples were subjected to radio TLC analysis (silica gel plate, 100% ethyl acetate extension) to determine the radiochemical conversion (RCC), by radioactive HPLC (60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C-18 Column) and radioactive TLC (silica gel plate, 100% ethyl acetate spread) to determine product identity and purity.
  • RRC radiochemical conversion
  • radioactive HPLC 60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C-18 Column
  • radioactive TLC silicon gel plate, 100% ethyl acetate spread
  • the radiochemical yield was determined as the percentage of radioactivity separated as the final product from the activity in the V-vial when the iodonium precursor was added to the DMF diluted [ 18 F]Et 4 NOMs solution, and there was no decay correction.
  • the uncorrected radiochemical yield of [ 18 F]-2-Larotrectinib is 28.56% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 18.21 Ci/ ⁇ mol).
  • the protective group removal rate is 95%.
  • the TLC tracking marker precursor I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction sample (1-2uL) was detected to have [ 18 F] -Bz-2-Larotrectinib labeled product.
  • the subsequent steps are the same as the first scheme, and the radiochemical purity and chemical purity of the obtained product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-2-Larotrectinib relative to the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi) and specific activity are shown in Table 3 below.
  • Anion exchange solid phase extraction cartridge (QMA) was put into a V-shaped vial, and the obtained acetonitrile solution of [ 18 F]Et 4 NOMs was dehydrated to dryness by repeated azeotropic evaporation with anhydrous acetonitrile, and the remainder was dried with different anhydrous solvents DMF (0.4mL ), DMSO (0.4 mL), DMA (0.4 mL), CH3CN (0.4 mL), NMP (0.4 mL) diluted to 10 mg/mL of [ 18 F]Et 4 NOMs solution.
  • the subsequent steps are the same as the first scheme, and the radiochemical purity and chemical purity of the obtained product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-2-Larotrectinib relative to the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi) and the specific activity are shown in Table 4 below.
  • the obtained acetonitrile solution of [ 18 F]Et 4 NOMs is dehydrated by anhydrous acetonitrile repeated azeotropic evaporation To dryness, the residue was diluted with anhydrous DMF (0.4 mL) to a 10 mg/mL solution of [ 18 F]Et 4 NOMs.
  • the subsequent steps are the same as the first scheme, and the radiochemical purity and chemical purity of the obtained product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-2-Larotrectinib relative to the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi) and the specific activity are shown in Table 5 below.
  • Scheme V The operation process is the same as Scheme I. The difference is that a 400uL sample is separated from the DMF solution and added to the V added with the labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib white solid (4.0mg) Type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35mCi). The mixture was heated to different temperatures of 100 °C, 110 °C, 120 °C, 135 °C, 145 °C, 155 °C, and 160 °C for 20 minutes respectively, TLC tracking labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib Basically disappeared.
  • Scheme 7 The operation process is the same as Scheme 1. The difference is that a 400uL sample is separated from the DMF solution and added to the V added with the labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib white solid (0.5mg) Type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35mCi). The mixture was heated to 120 °C, 135 °C, 145 °C, 155 °C, and 160 °C for 5 min, 10 min, 15 min, and 20 min, respectively. TLC traced the precursor I(III)-SPIAd-Bz-2-Larotrectinib Basically disappeared.
  • a 400 uL sample was separated from the above DMF solution and added to a V-shaped reaction flask ([ 18 F]Et 4 NOMs) added with a labeled precursor I(III)-SPIAd-Bz-2-Larotrectinib white solid (1.0 mg) Usually 1.35mCi).
  • the mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Bz-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -Bz-2-Larotrectinib labeled product.
  • the samples were subjected to radio TLC analysis (silica gel plate, 100% ethyl acetate extension) to determine the radiochemical conversion (RCC), by radioactive HPLC (60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C-18 Column) and radioactive TLC (silica gel plate, 100% ethyl acetate spread) to determine product identity and purity.
  • RRC radiochemical conversion
  • radioactive HPLC 60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C-18 Column
  • radioactive TLC silicon gel plate, 100% ethyl acetate spread
  • the radiochemical yield was determined as the percentage of radioactivity separated as the final product from the activity in the V-vial when the iodonium precursor was added to the DMF diluted [ 18 F]Et 4 NOMs solution, and there was no decay correction.
  • the uncorrected radiochemical yield of [ 18 F]-2-Larotrectinib is 41.82% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 27.11Ci/ ⁇ mol).
  • [18F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Bz-5-Larotrectinib, the deprotection rate of the product was 100%, the radiochemical purity and chemical purity of the product> 99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib was 41.15% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity was obtained in the final formulation ( 27.13Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker take [ 18 F]fluorine source (0.5 mL, activity meter measurement (t 0 ) activity 1.5mCi) QAM[ 18 F]fluoride, use N,N, Ammonium N,N-tetraethylmethanesulfonate (TBAOMs, 8.0 mg) was dissolved in a solution of 1 mL of acetonitrile to elute the fluorine source QAM [ 18 F] fluoride anion exchange solid phase extraction cartridge (QMA) into a V-shaped vial.
  • QMA N,N, Ammonium N,N-tetraethylmethanesulfonate
  • a 400 uL sample was separated from the above DMF solution and added to a V-shaped reaction flask ([ 18 F]Et 4 NOMs) added with a labeled precursor I(III)-SPIAd-TBS-2-Larotrectinib white solid (1.0 mg) Usually 1.35mCi).
  • the mixture was heated to 155 degrees for 12 minutes under confinement, and the TLC tracking marker precursor I(III)-SPIAd-TBS-2-Larotrectinib basically disappeared.
  • the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -2-Larotrectinib labeled product.
  • the reaction was further diluted with HPLC buffer (60:40 CH 3 CN:H 2 O+0.1N ammonium formate, 2 mL), and the Waters C-activated by rinsing with ethanol (1 mL) and water (5 mL) successively 18 Sep-Pak.
  • Rinse Sep-Pak with water (2mL) elute the desired product with ethanol (1mL)
  • rinse into a sterile vacuum bottle blow dry with nitrogen at 60 degrees for 20 minutes, reconstitute with brine, which contains 100ul, 25% Vitamin C in water, 100ul, 20% Tween 80 in ethanol, to obtain [ 18 F]-2-Larotrectinib marker injection.
  • the samples were subjected to radio TLC analysis (silica gel plate, 100% ethyl acetate extension) to determine the radiochemical conversion (RCC), by radioactive HPLC (60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C-18 Column) and radioactive TLC (silica gel plate, 100% ethyl acetate spread) to determine product identity and purity.
  • RRC radiochemical conversion
  • radioactive HPLC 60:40 CH 3 CN:H 2 O+0.1N ammonium formate, Phenomenex Luna C-18 Column
  • radioactive TLC sica gel plate, 100% ethyl acetate spread
  • the radiochemical yield was determined as the percentage of radioactivity separated as the final product from the activity in the V-vial when the iodonium precursor was added to the DMF diluted [ 18 F]Et 4 NOMs solution, and there was no decay correction.
  • the uncorrected radiochemical yield of [ 18 F]-2-Larotrectinib is 45.82% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.82Ci/ ⁇ mol).
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-TBS-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.21% with respect to the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.81Ci/ ⁇ mol).
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-SEM-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.55% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.80Ci/ ⁇ mol).
  • reaction mixture was neutralized with 5N sodium hydroxide (5N, 0.2 mL) and diluted with HPLC mobile phase (10% ethanol, 28 mM hydrochloric acid, 20 nM ammonium acetate, pH 2, 0.5 mL).
  • the mixture (2uL) was subjected to TLC thin-layer chromatography (expansion agent: 100% ethyl acetate) to determine the labeling rate (RCC), then diluted with 15mL of water, and passed through a solid phase extraction cartridge of C18 packing, and eluted with water (24mL). Acetonitrile (1.5 mL) was rinsed and collected in a micro bottle.
  • the mixture (20 uL) and fluorine-19 standard control ( 19 F-Larocetrinib) were co-injected into the radio HPLC to determine the fluorine-18 labeled product ( 18 F-Larocetrinib).
  • the remaining reaction mixture was neutralized with 5N sodium hydroxide (5N, 0.2 mL) and diluted with HPLC mobile phase (10% ethanol, 28 mM hydrochloric acid, 20 nM ammonium acetate, pH 2, 0.5 mL).
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-TBDPS-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib relative to the V-type reaction flask [ 18 F]Et 4 NOMs is usually 1.35 mCi) is 45.50%, and the specific activity is obtained in the final formulation ( 29.83 Ci/ ⁇ mol).
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-TIPS-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.23% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.31Ci/ ⁇ mol).
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-TPIS-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.27% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.31Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400 uL sample was separated from the DMF solution and added to a V-shaped reaction flask with white solid (1.0 mg) labeled precursor I(III)-SPIAd-Piv-2-Larotrectinib ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Piv-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -Piv-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Piv-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.64% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.44Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-Ac-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement, and the TLC tracking label precursor I(III)-SPIAd-Ac-2-Larotrectinib basically disappeared. The radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -Ac-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Ac-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.54% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.25Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. 400uL sample was separated from the DMF solution was added to the labeling precursor I (III) -SPIAd-Tf- 2-Larotrectinib as a white solid (1.0 mg of) a V-type reaction flask is added ([18 F] Et 4 NOMs generally It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Tf-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction sample (1-2uL) was detected to have [ 18 F]-Tf -2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Tf-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.78% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.54Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-CAc-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-CAc-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -CAc-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeled precursor I(III)-SPIAd-CAc-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.25% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.12Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to a V-shaped reaction flask with a labeled precursor I(III)-SPIAd-DCAc-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi).
  • TLC tracking marker precursor I(III)-SPIAd-DCAc-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction sample (1-2uL) was detected to have [ 18 F] -DCAc-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-DCAc-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.53% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.24Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-Moc-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Moc-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -Moc-2-Larotrectinib labeled product.
  • Potassium hydroxide (KOH, 0.37 mg) was added to the reaction mixture, heated to 100 degrees for 12 minutes, the reaction was cooled in an ice bath at 0°C, and then 10% aqueous HCl solution was added dropwise to the solution and neutralized. The subsequent operations are the same as in Example 92.
  • the deprotection conversion rate is more than 89.8%.
  • the radiochemical purity of the product is greater than 96.3%, and the chemical purity is greater than 91.3%.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Moc-5-Larotrectinib.
  • the deprotection rate of the product was 89%, the radiochemical purity of the product was >96%, and the chemical purity was >91%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 35.56% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 22.23 Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-Eoc-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Eoc-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction sample (1-2uL) was detected to have [ 18 F] -Eoc-2-Larotrectinib labeled product.
  • Potassium hydroxide (KOH, 0.37 mg) was added to the reaction mixture, heated to 100 degrees for 12 minutes, the reaction was cooled in an ice bath at 0°C, and then 10% aqueous HCl solution was added dropwise to the solution and neutralized. The subsequent operations are the same as in Example 92.
  • the deprotection conversion rate is above 90.2%.
  • the radiochemical purity of the product is greater than 97.5%, and the chemical purity is greater than 90.1%.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Eoc-5-Larotrectinib.
  • the deprotection rate of the product is 90%, the radiochemical purity of the product is >97%, and the chemical purity is >90%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 32.35% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 21.14 Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-Boc-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Boc-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -Boc-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Boc-5-Larotrectinib.
  • the deprotection rate of the product is 100%, and the radiochemical purity and chemical purity of the product are >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 45.35% relative to that in a V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 29.51Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400 uL sample was separated from the DMF solution and added to a V-shaped reaction flask with white solid (1.0 mg) labeled precursor I(III)-SPIAd-Troc-2-Larotrectinib ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement, and the TLC tracking marker precursor I(III)-SPIAd-Troc-Larotrectinib basically disappeared. The radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F]-Troc -2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Troc-5-Larotrectinib.
  • the deprotection rate of the product is 95%, the radiochemical purity of the product is >97.5%, and the chemical purity is >97.5%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 38.35% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 25.41 Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400 uL sample was separated from the DMF solution and added to a V-shaped reaction flask with white solid (1.0 mg) labeled precursor I(III)-SPIAd-PMB-2-Larotrectinib ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement, and the TLC tracking marker precursor I(III)-SPIAd-PMB-2-Larotrectinib basically disappeared. The radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -PMB-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-PMB-5-Larotrectinib.
  • the deprotection rate of the product is 95%, the radiochemical purity of the product is >97.5%, and the chemical purity is >97.5%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 38.35% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 25.40Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400 uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-PMP-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-PMP-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -PMP-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-PMP-5-Larotrectinib.
  • the deprotection rate of the product is 93%, the radiochemical purity of the product is >95.5%, and the chemical purity is >91.5%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 37.65% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 23.81 Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400 uL sample was separated from the DMF solution and added to a V-shaped reaction flask with white solid (1.0 mg) labeled precursor I(III)-SPIAd-MOM-2-Larotrectinib ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-MOM-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -MOM-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-MOM-5-Larotrectinib.
  • the deprotection rate of the product was 93%, the radiochemical purity of the product was >95.8%, and the chemical purity was >91.8%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 36.25% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 22.27Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400 uL sample was separated from the DMF solution and added to a V-shaped reaction flask with white solid (1.0 mg) labeled precursor I(III)-SPIAd-MEM-2-Larotrectinib ([ 18 F]Et 4 NOMs usually It is 1.35mCi).
  • TLC tracking marker precursor I(III)-SPIAd-MEM-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -MEM-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-MEM-5-Larotrectinib.
  • the deprotection rate of the product is 97%, the radiochemical purity of the product is >96%, and the chemical purity is >96%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 37.25% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 23.21 Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to a V-shaped reaction flask ([ 18 F]Et 4 NOMs usually added with labeled precursor I(III)-SPIAd-THP-2-Larotrectinib white solid (1.0 mg) It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-THP-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -THP-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-THP-5-Larotrectinib.
  • the deprotection rate of the product is 97%, the radiochemical purity of the product is >99%, and the chemical purity is >97%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib was 41.55% relative to that in the V-type reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity was obtained in the final formulation ( 27.81Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-EE-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement, and the TLC tracking marker precursor I(III)-SPIAd-EE-2-Larotrectinib basically disappeared. The radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -EE-2-Larotrectinib labeled product.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-EE-5-Larotrectinib.
  • the deprotection rate of the product is 100%, the radiochemical purity of the product is >99%, and the chemical purity is >99%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib relative to the V-type reaction flask [ 18 F]Et 4 NOMs is usually 1.35 mCi) is 45.50%, and the specific activity is obtained in the final formulation ( 28.51Ci/ ⁇ mol).
  • [ 18 F]-Larotrectinib marker a solution of [ 18 F]Et 4 NOMs (20 mg/mL, 0.4 mL) of anhydrous DMF was prepared. A 400uL sample was separated from the DMF solution and added to the V-shaped reaction flask with the labeled precursor I(III)-SPIAd-Als-2-Larotrectinib white solid (1.0 mg) ([ 18 F]Et 4 NOMs usually It is 1.35mCi). The mixture was heated to 155 degrees for 12 minutes under confinement.
  • the TLC tracking marker precursor I(III)-SPIAd-Als-2-Larotrectinib basically disappeared, and the radioactive TLC tracking reaction mixture sample (1-2uL) was detected to have [ 18 F] -Als-2-Larotrectinib labeled product.
  • Morpholine and 35% formic acid solution (1:1, 1.84mg) were added to the reaction mixture, a catalytic amount of tetraphenylphosphorpalladium was added, heated to 80 degrees, 8 minutes, the reaction was cooled in an ice bath at 0°C, and then added A 10% NaHCO 3 aqueous solution was added dropwise to the solution and neutralized.
  • the subsequent operations are the same as in Example 92.
  • the deprotection conversion rate is greater than 99%.
  • the radiochemical purity of the product is greater than 96.5%, and the chemical purity is greater than 96.7%.
  • [ 18 F]-5-Larotrectinib marker was prepared from the labeling precursor I(III)-SPIAd-Als-5-Larotrectinib.
  • the deprotection rate of the product is greater than 99%, the radiochemical purity of the product is >97%, and the chemical purity is >97%.
  • the uncorrected radiochemical yield of [ 18 F]-5-Larotrectinib is 41.75% relative to that in the V-shaped reaction flask ([ 18 F]Et 4 NOMs is usually 1.35 mCi), and the specific activity is obtained in the final formulation ( 26.71Ci/ ⁇ mol).

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Abstract

一种放射性氟标记Larotrectinib化合物及其制备方法，特别是难治性实体瘤中，Trk受体亚型的体内显像剂，提供基于新型的针对酪氨酸受体激酶(TRK)的抑制剂Larotrectinib的放射性氟化合物 18F-Larotrectinib及其 18F-Larotrectinib类似物，更特别涉及一种Larotrectinib及其类似物放射性氟-18标记化合物 18F-Larotrectinib及其 18F-Larotrectinib类似物的制备方法。与现有技术相比，具有反应速度快，条件相对温和，操作简单，反应时间短，后处理简单，可制备得到无载体放射性标记化合物，放化纯度高，具有发射正电子的特性，借助PET-CT正电子发射断层显像技术，直观显示Larotrectinib化合物及其类似物在活体内，以及肿瘤中的分布状况，并为肿瘤早期诊断提供一种新的显像剂。

Description

一种放射性氟标记Larotrectinib化合物及其制备方法 技术领域
本发明涉及化学药物合成领域，特别是难治性实体瘤中，Trk受体亚型的体内显像剂，具体涉及基于新型的针对酪氨酸受体激酶(TRK)的抑制剂Larotrectinib的放射性氟化合物 18F-Larotrectinib及其 18F-Larotrectinib类似物,更特别涉及一种Larotrectinib及其类似物放射性氟-18标记化合物 18F-Larotrectinib及其 18F-Larotrectinib类似物的制备方法。
背景技术
Larotrectinib是由Loxo Oncology公司研发，作为一款广谱肿瘤药，用于所有表达有原肌球蛋白受体激酶(tropomyosin receptor kinase，TRK)的肿瘤患者，这种TRK小分子抑制剂对TRK有很强的选择性，通过抑制TRK信号通路，larotrectinib可以抑制肿瘤的生长。larotrectinib是一种口服的强力TRK抑制剂，在TRK融合肿瘤中具有一致和持久的抗肿瘤活性，适用的患者年龄和肿瘤类型范围广，其适应症分布于13种不同肿瘤类型，并且具有良好的耐受性，对多种成人和儿童实体瘤有效，包括唾液腺癌(salivary)、婴儿纤维肉瘤癌(infantile fibrosarcoma)、肺癌(lung)、甲状腺癌(thyroid)、结肠癌(colon)、黑色素瘤(melanoma)、胆管癌(cholangio)、肠胃癌(GIST)、乳腺癌、以及各种肉瘤癌(sarcoma)。美国 FDA(http://www.chemdrug.com/article/11/)已经授予larotrectinib孤儿药资格和突破性药物资格认定。Larotrectinib有望成为第一个在成人和儿童中同时开发和批准的治疗药物，并且是第一种跨越所有传统定义的肿瘤类型、分子意义上的肿瘤靶向治疗药。Larotrectinib的结构如下所示：
Figure PCTCN2019106690-appb-000001
然而，目前对于药物分子在体内的分布及疗效评价，通常采用发射正电子 的放射性药物18F-脱氧葡萄糖(18F-FDG)，间接评价药物对肿瘤及相关疾病的疗效，而且，发射正电子的放射性药物18F-脱氧葡萄糖(18F-FDG)在非肿瘤组织和炎症细胞成分中也有较高的FDG吸收，致使FDG用于肿瘤显像时可能因为存在炎症而造成肿瘤诊断的假阳性结果。因此，如何在活体内在线示踪Larotrectinib在人体内或动物体内分布以及实体瘤中的状况，直观判断Larotrectinib在肿瘤中的生理功能，评判其疗效及其愈后效果，这是一个棘手的难题。
PET(Positron emission tomography)是一种非浸入性显像技术，具有在活体内分子水平上实现药物分子生理生化功能、药理学过程的可视化和定量化评估。Larotrectinib分子作为一种原肌球蛋白受体激酶(tropomyosin receptor kinase，TRK)的小分子抑制剂，对TRK有很强的选择性，可用作PET显像分子，精准定位Larotrectinib分子在活体内评价肿瘤状况，实现在线示踪Larotrectinib分子在动物或人体内分布以及实体瘤中的状况，直观判断Larotrectinib在动物体、人体内以及肿瘤中的生理功能和药理学过程，评判其疗效及其愈后效果，目前尚未见有更为有效的技术手段。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种[ 18F]-标记Larotrectinib化合物及其制备方法。
本发明的目的可以通过以下技术方案来实现：一种[ 18F]-标记Larotrectinib化合物，其特征在于，包括具有以下结构式 18F-Larotrectinib化合物及其类似物：
Figure PCTCN2019106690-appb-000002
Figure PCTCN2019106690-appb-000003
上述所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，该方法包括以下步骤：
步骤一：羟基保护：碘代Larotrectinib类似物前体(I-Larotrectinib)的活性羟基官能团的保护；
步骤二：标记前体制备：碘代Larotrectinib类似物前体(I-Larotrectinib)碘的活化制备三氟醋酸碘代Larotrectinib类似物，随后与金刚烷取代的辅助酸反应制备标记前体：螺环高价碘(III)代羟基保护的Larotrectinib类似物；
步骤三：氟-18标记产物的制备：标记前体与氟-18放射性源取代反应，制备羟基保护的18F-Larotrectinib的合成及18F-Larotrectinib类似物的合成，随后脱保护得到18F-Larotrectinib及18F-Larotrectinib类似物。
18F-2-Larotrectinib的合成路线如下：
Figure PCTCN2019106690-appb-000004
Figure PCTCN2019106690-appb-000005
18F-5-Larotrectinib的合成路线与上述 18F-2-Larotrectinib相同：只是原料中碘代Larotrectinib类似物前体(I-Larotrectinib)中I的取代位置为5位取代，具体合成路线如下：
Figure PCTCN2019106690-appb-000006
步骤一所述的碘代Larotrectinib类似物前体包括如下结构式：
Figure PCTCN2019106690-appb-000007
上式中，R1、R2分别独立代表苯基取代基，R1、R2各自独立地选自H、卤素、羟基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C6-10芳基、C4-10杂环烷基、C6-10杂芳基组成的组；R1、R2各自独立地与R3组成组；
上式中，R3具体代表为H；所述的活性羟基官能团的保护是指通过酯化反应或醚化反应，将R3通过以下官能团取代，从而保护活性羟基，取代的官能团包括三甲基硅氧醚(TMS)、叔丁基二甲基硅氧烷醚(TBDMS)、三乙基硅氧醚(TES)、叔丁基二苯基硅氧烷醚(TBDPS)、甲醚(Me)、苄醚(Bn)、三苯甲基醚(Tr)、对甲氧基三苯甲基醚(MMT)、二甲氧基三苯甲基醚(DMT)、叔丁基醚(tBu)、甲氧基甲醚(MOM)、2-甲氧基乙氧基甲基醚(MEM)、甲硫基甲醚(MTM)、苄氧基甲基醚(BOM)、对甲氧基苄基醚(PMB)、对甲氧基苄氧基甲基醚(PMBOM)、3,4-二甲氧基苄基醚(DMB)、四氢吡喃醚(THP)、甲氧羰基(Moc)、乙氧羰基(Eoc)、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、9-芴甲氧基羰酰基(Fmoc)、乙酰基(Ac)、三氟乙酰基(TfAc)、氯乙酰基(CAc)、二氯乙酰基(DCAc)、苯甲酰基(Bz)、特戊酰基(Pv)、甲磺酰基(Ms)、苄基磺酸酰基(Bs)、烯丙基磺酸酰基(Bs)、烯丙基氧羰基(Als)、烯丙氧羰基、C1-16烷酰基、C2-16烯酰基、C3-6炔酰基、C4-10环烷基、C7-16芳酰基、C4-10杂环烷酰基；且可任选被1、2、3或4个独立的R3基团取代，所述的烷酰基优选乙酰基；所述的芳酰基优先苯甲酰基；可任选被1、2、3或4个独立的R3基团取代，所述的取代烷酰基，特戊酰基或苯乙酰基。
步骤二所述的三氟醋酸碘代Larotrectinib类似物的制备是将步骤一制得的活性羟基被保护的碘代Larotrectinib类似物前体(I-Larotrectinib)，与三氟乙酸或三氟乙酸酐、有机溶剂、氧化剂进行反应，使I被三氟醋酸根活化；
所述的有机溶剂包括氯仿、二氯甲烷、乙腈、丙酮、过氧化叔丁醇中的一 种或几种；
所述的氧化剂包括脲-过氧化氢复合物、Oxone、2,2,6,6-四甲基哌啶-氧化物或mCPBA。
步骤二所述的金刚烷取代的辅助酸为SPIAd，SPIAd与三氟醋酸碘代Larotrectinib类似物反应的条件为：SPIAd与碳酸钠溶液、MeCN、NaHCO3和丙酮中的一种或几种在0℃混合，并控制混合液pH值为8～10，与三氟醋酸碘代Larotrectinib类似物在0℃连续搅拌反应1～10h得到标记前体。
步骤三所述的氟-18放射性源通过以下方法获得：
(1)制备[ 18F]氟化物靶水：[ 18F]氟化物靶水通过1 8O(p,n) 18F核反应生产，使用GE PETTrace回旋加速器，通过氮气压力将[ 18F]氟化物靶水递送到 18O-富集水的无菌铅保护热室；用这种方法生产的[ 18F]氟化物靶水在用于研究之前,通常用Milli-Q(密理博公司超纯水仪器)超纯化水进一步稀释成1-3mCi/毫升[ 18F]氟化物靶水液体；
(2)QMA阴离子交换固相萃取盒(QMA)富集[ 18F]氟化物：将含有适量的[ 18F]氟化物的目标水的等分试样,在氮气流冲洗下，缓慢通过阴离子交换固相萃取盒(QMA)，该阴离子交换固相萃取盒(QMA)事先使用NaHCO 3(aq)(8.4％，1mL)和水(20mL，直到pH指示剂为中性)冲洗而预活化，将[ 18F]氟化物富集在QMA阴离子交换固相萃取盒(QMA)上，将 18O和其它不纯物分离洗脱除去，得到[ 18F]氟化物QMA阴离子交换固相萃取盒(QMA)的[ 18F]氟源；
(3)洗脱QMA阴离子交换固相萃取盒(QMA)上富集的[ 18F]氟化物，得到[ 18F]氟化物季铵盐或无机盐溶液：使用冲洗液有机或无机碱(例如，一定数量的四乙基碳酸氢铵，例如8mg)溶解在乙腈和水(1mL，v/v 7:3)或乙腈(1mL)或甲醇(1mL)或乙醇(1mL)中所得的溶液，冲洗富集在QMA阴离子交换固相萃取盒(QMA)上的[ 18F]氟化物，将[ 18F]氟化物洗脱到用特氟隆衬垫隔膜密封的V形小瓶中，得到[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇溶液；
(4)制备干燥的[ 18F]氟化物季铵盐或无机盐：将装有[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇或乙醇溶液的特氟隆衬垫隔膜密封的V形小瓶加热至95-110℃，同时使氮气通过P 2O 5-Drierite TM柱干燥后吹扫V形小瓶，随后通过通气的小瓶排出尾气；当在小瓶中没有液体可见时，将其从热浴中取 出，添加无水乙腈(1mL)，并恢复加热直至干燥，将该步骤重复另外三次；然后将小瓶在氮气流下，在室温下冷却，得到干燥的[ 18F]氟化物有机盐或无机盐，包括[ 18F]KF/K 2CO 3/K 2.2.2、[ 18F]KF/K 2C 2O 4/K 2.2.2、[ 18F]KF/KOTf、[ 18F]Et 4NF、[ 18F]Et 4NHCO 3、[ 18F]Et 4NOMs、[ 18F]Et 4NOTf，其放射性[ 18F]氟化物回收率，根据采用的洗脱工艺不同而有差异。
步骤三所述的标记前体与氟-18放射性源取代反应：取装有干燥的[ 18F]氟化物有机盐或无机盐的V形小瓶，添加溶剂重新溶解，再添加标记前体，进行反应，得到[ 18F]-Larotrectinib未脱保护的标记物的粗品反应液。
步骤三所述的脱保护通过以下方法实现：采用不添加或添加一定量的有机碱或无机碱或有机酸或无机酸至[ 18F]-Larotrectinib未脱保护的标记物的粗品反应液中，在加热条件下脱除羟基保护基，得到[ 18F]-Larotrectinib标记物的粗品反应液。
所述的[ 18F]-Larotrectinib标记物的粗品反应液还需要通过以下方法进行分离纯化：将[ 18F]-Larotrectinib标记物的粗品反应液通过采用半制备HPLC或Waters Sep-Pak C-18小柱纯化，并用溶剂淋洗进无菌真空瓶，60℃下氮气吹干20分钟，用盐水重新复配，其中含有100ul，25％的维生素C的水溶液，100ul，20％吐温80的乙醇溶液，即得[ 18F]-Larotrectinib标记物注射液，该[ 18F]-Larotrectinib标记物注射液通过以下方法进行分析鉴定：
通过放射性HPLC(60:40 CH 3CN:H 2O+0.1N甲酸铵，Phenomenex Luna C 18,250×4.6mm,5μm,UV at 254nm；CH 3CN/0.1M NH4·HCO 2(aq)(v/v,7/3)，流速1.0mL/min)和放射性TLC(EtOAc+0～5％EtOH)测定产物标识和纯度(放射化学纯度和化学纯度)。产物的放射化学纯度>90-99％。产物的化学纯度>90-99％。将放射化学产率确定为从在将标记前体加入DMF稀释的[ 18F]Et 4NHCO 3溶液的V型小瓶中的活度量作为最终产物分离的放射性的百分比，并且没有衰变校正。放射化学得率20～45.3(未经衰减校正)，放射化学纯度大于99％，比活度2.56～18Ci/μmol)。
与现有技术相比，本发明具有以下有益技术效果：
(1)本发明提供一种氟-18标记的 18F-Larotrectinib化合物及其类似物，并且提供一种氟-18标记的Larotrectinib化合物及其类似物的制备方法，即采用三 价碘取代法制备氟-18标记的 18F-Larotrcetinib，反应速度快，条件相对温和，操作简单，反应时间短，后处理简单，可制备得到无载体放射性标记化合物，放化纯度高。
(2)本发明提供一种氟-18标记的 18F-Larotrectinib化合物及其类似物，具有发射正电子的特性，借助PET-CT正电子发射断层显像技术，直观显示Larotrectinib化合物及其类似物在活体内，以及肿瘤中的分布状况，并为肿瘤早期诊断提供一种新的显像剂。
具体实施方式
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。下述实例中所用的材料、试剂、装置、仪器、设备等，如无特殊说明，均可从商业途径获得。
其中步骤一所述的碘代Larotrectinib类似物前体
Figure PCTCN2019106690-appb-000008
上式中，R3具体代表为H。
可以通过以下方法制得：
步骤一：关键中间体4及其合成
Figure PCTCN2019106690-appb-000009
步骤二：关键中间体8及其合成
Figure PCTCN2019106690-appb-000010
步骤三：卤代Larotrectinib类似物9的制备
Figure PCTCN2019106690-appb-000011
以(R)-2-F-5-I-Larotrectinib的制备为例进行说明，其制备方法如下：
步骤一：关键中间体4及其合成
1a、(E)-4-(5-fluoro-2-iodophenyl)-4-oxobut-2-enoic acid的合成
Figure PCTCN2019106690-appb-000012
在500mL反应器中，加入5-氟-2-碘苯乙酮(39.6g,150mmol),乙醛酸单水合物(13.9g,151mmol),加热反应并减压蒸出水(95度，0.1Mpa),反应3小时，反应混合物冷却至室温，加入5％碳酸钾水溶液(300mL),用乙酸乙酯萃取2次，每次200mL,水层酸化(10％盐酸，300mL)后,乙酸乙酯萃取2次，每次200mL,合并有机相，盐水洗涤，无水硫酸钠干燥，减压去溶剂，得到橘黄色固 体。固体溶于冰醋酸(50mL),浓盐酸(36％,5mL)，混合物加热回流4小时，减压去醋酸，剩余物用乙酸乙酯萃取(300mL)，盐水洗涤3次，每次100mL,有机相无水硫酸钠干燥，减压去溶剂，得到目标产物(26.89g,56％)黄色固体,M.P.146度。
1H NMR(400MHz,DMSO-d6)δ12.96(brs,1H),8.00-7.74(m,3H),7.30(t,1H,J＝8.5Hz),6.64(d,1H,J＝15.4Hz)。
MS(EI)m/z 320(M+)
1b、4-(5-fluoro-2-iodophenyl)-4-oxobutanoic acid的合成
Figure PCTCN2019106690-appb-000013
在500mL反应瓶中，加入醋酸210mL，水75mL，起始物料(47.1g,147mmol),搅拌下，向反应混合物中分批次添加锌粉(10.9g，166mmol)，约1小时加完，混合物继续搅拌3小时，反应物过滤，滤饼用乙酸乙酯(300mL)漂洗,有机相用盐水洗涤3次，每次100mL,无水硫酸钠干燥，减压去溶剂，得到目标产物(29.8g,63％)。M.P.152度。
1H NMR(400MHz,CDCl 3)12.00(1H,brs),7.91-7.71(3H,m),3.23(2H,t,J＝6.26),2.57(2H,t,J＝6.24).
MS(EI)m/z 322(M+).。
1c、methyl 4-(5-fluoro-2-iodophenyl)-4,4-dimethoxybutanoate的合成
Figure PCTCN2019106690-appb-000014
在250mL反应瓶中，加入起始物料(32.2g,0.1mol)，原甲酸三甲酯(C4H10O3＝106.12,31.84g，0.3mol),甲醇(90mL),滴加10滴硫酸，升温至65度反应4小时，TLC跟踪反应过程，至起始原料转化完全，减压蒸馏去溶剂，剩余物用异丙醚稀释(190mL),饱和碳酸氢钠淬灭反应(100mL)，有机相分层，盐水 洗涤2次，每次(120mL),无水硫酸镁干燥，蒸去溶剂，得到产物32.48g，收率85％，直接用于下一步。
1H NMR(400MHz,CDCl 3)1.29-1.38(2H,m),2.25(2H,t,J＝7.2Hz),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＝8.6,1.4Hz)；
MS(ESI)m/z 383[M+H] +。
1d、4-(5-fluoro-2-iodophenyl)-4-oxobutanamide的合成
Figure PCTCN2019106690-appb-000015
在250mL反应瓶中，加入甲醇100mL，降温至0度以下，通入氨气至饱和(大约10-12g)，将1c步骤酯化产物(19.1g，0.05mol)，溶解在50mL甲醇中得到的液体，滴加到甲醇-氨的饱和溶液中，保持内温0度左右。滴加完毕，反应液在零度下继续反应16小时。TLC检测反应液至1c步骤酯化产物基本消失时，停止反应，减压去溶剂，得到油状物直接用于下步反应。
MS(ESI)m/z:368.1(M+H)+.。
1e、5-(5-fluoro-2-iodophenyl)-3,4-dihydro-2H-pyrrole的合成
Figure PCTCN2019106690-appb-000016
在500mL反应器中，加入干燥的四氢呋喃(300mL)、1d步骤所得酰胺(18.36g,0.05mol)、硼氢化钠(29.26g，0.77mol)，搅拌均匀，并用冰浴冷却至零度，氮气保护下，滴加三氟化硼乙醚溶液(36.75mL，0.3mol),大约2小时左右滴加完毕，撤去冰浴，混合物升温至回流16小时，TLC检测原料转化完全，反应液冷却至5度，缓慢滴加6N盐酸(35mL),混合物升温至回流1小时，反应液冷却至40度，减压去溶剂，剩余物加水稀释，10％NaOH中和至中性， 氯仿萃取，无水硫酸钠干燥，过滤减压浓缩得到油状的5-(5-氟-2-碘苯)-3，4-二氢-2H-吡咯(11.27g，收率78％)。
所得产品核磁数据如下：
1H NMR,400MHz,CD 3ODδ:7.78(m,1H),7.43-7.34(m,2H),3.54(m,2H),2.12(dt,J＝10.3,2.0Hz,2H),1.97(dt,J＝15.8,7.9Hz,2H).
13C NMR,100MHz,CD 3ODδ: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.。
1f、2-(5-fluoro-2-iodophenyl)pyrrolidine的合成
Figure PCTCN2019106690-appb-000017
将油状5-(5-氟-2-碘苯)-3，4-二氢-2H-吡咯(7.23g，0.025mol)溶解在100mL甲醇和水(4:1)的溶液中，降温至0度，分批添加硼氢化钠(0.95g，0.025mol),有氢气放出，反应液成黄色浊液，3小时后升至室温，蒸馏去溶剂，剩余物用NaOH处理后，异丙醚萃取，醚层经过无水硫酸钠干燥过夜，过滤去溶剂，得到淡黄色油状物(6.23g，收率88.3％)，直接投下步反应。
1H NMR,400MHz,CDCl 3δ:7.29(m,1H),7.02(m,1H)，6.96(m,1H),4.09(t,J＝7.8Hz，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)。
LC-ESI-MS(m/z)292[M+H] +。
第二步：关键中间体8的合成:
2a、5-chloropyrazolo[1,5-a]pyrimidin-3-amine的合成
Figure PCTCN2019106690-appb-000018
在1000mL反应瓶中，加入5-chloro-3-nitropyrazolo[1,5-a]pyrimidine化合物(25g,0.125mol)、乙醇(250mL)、和铁粉(75g，1.25mol)加入到反应瓶中，氮气保护下，加热至回流，同时滴加氯化铵(66.5g,1.25mol)水溶液(250mL)，大约1小时滴加完毕，继续回流反应6小时,TLC跟踪至反应完毕后，减压浓缩至糊状， 加入水(100mL)稀释剩余物，添加二氯甲烷分层，萃取4-6次，每次200mL，合并有机相，用饱和食盐水洗涤，用无水硫酸镁干燥，减压浓缩得到5-chloropyrazolo[1,5-a]pyrimidin-3-amine化合物419.7g，收率为93.5％。
1H NMR,400MHz,CD 3ODδ:9.29(d,J＝7.2Hz,1H),8.71(s,1H),8.16(d,J＝7.2Hz,1H),5.92(s,2H)；
MS(ESI)m/z:169.8[M+H]+。
2b、5-chloro-3-isocyanatopyrazolo[1,5-a]pyrimidine的合成
Figure PCTCN2019106690-appb-000019
将三光气(9.91g,33.38mmol)溶解于50ml四氢呋喃中，加入5-chloropyrazolo[1,5-a]pyrimidin-3-amine(16.86g,0.1mol)和三乙胺(0.47g,4.64mmol),反应体系于25度搅拌反应1小时。得到5-chloro-3-isocyanatopyrazolo[1,5-a]pyrimidine的悬浮液，产物不经过纯化直接进行下一步反应。
2c、(S)-N-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide的合成
Figure PCTCN2019106690-appb-000020
在250mL反应器中,加入碳酸氢钠溶液(80ml,0.5M，40mmol)，加入(S)-吡咯-3-醇(79g,55mmol),滴加步骤9b制备的异氰酸酯溶液(62mL,100mmol以5-chloropyrazolo[1,5-a]pyrimidin-3-amine计),维持温度在0度左右，滴加完毕，混合物在0度下继续搅拌3小时后，加热至50度，继续反应5小时，冷却至室温，加入乙酸乙酯萃取3次，每次100mL。合并有机相，有机相用2N盐酸洗涤，盐水洗涤，无水硫酸钠干燥，过滤减压浓缩，剩余物经过硅胶柱层析，以乙酸乙酯/石油醚(5：5，v/v)洗脱，得产物22g，收率78％。
1H NMR(300MHz,d 6DMSO)δ：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)；
MS(ESI)m/z:282[M+H]+。
第三步：卤代Larotrectinib类似物9的制备
卤代Larotrectinib化合物(R)-5-F-2-I-Larotrectinib的合成
Figure PCTCN2019106690-appb-000021
将吡唑并(1，5a)嘧啶化合物(30g，106mmol)、5-F-2-I-吡咯化合物(30.9g，106mmol)和1，4-二氧六环(150mL)加入反应烧瓶中，滴加N，N-二甲基吡啶(C7H10N2＝122.17，25.9g，212mmol)，保持反应温度在30℃以内，滴加完毕后，继续反应6小时，TLC中控至反应完毕，后处理同实施例六，得到外消旋混合物5-F-2-I-Larotrectinib类白色固体53.8g，收率94.6％。然后通过手性LC分离纯化，得到(R)-5-F-2-I-Larotrectinib为手性纯白色固体、以及(S)-5-F-2-I-Larotrectinib为手性纯白色固体。
1H NMR(300MHz,d  6DMSO)δ＝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)；
MS(ESI)m/z:536.3(M+H)+。
下面分别通过实施例对本发明化合物的制备过程进行详细说明，其中
实施例1～42为第一步羟基保护，制备I羟基保护Larotrectinib化合物
实施例1
苯甲酰氯酯化，制备I-Bz-2-Larotrectinib或I-Bz-5-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，加入吡啶(240mmol,18.98g)，同时添加苯甲酰氯 (80mmol，11.4g)，混合物室温搅拌反应3小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，依次用稀HCl(除去吡啶；同时让未反应的酰氯变成酸)、再用稀的NaOH(最好饱和碳酸氢钠,100mL)洗除酸、饱和氯化钠洗涤至中性，并除去有机层大部分水。有机层经过无水硫酸钠干燥，减压浓缩去溶剂，剩余物用乙醇-甲基叔丁基醚(4：1，180mL)结晶，得到产物白色固体I-Bz-2-Larotrectinib，收率88％(70.4mmol，45.1g)。合成路线如下所示：
Figure PCTCN2019106690-appb-000022
实施例2
苯甲酰氯酯化，制备I-Bz-5-Larotrectinib
制备方法同实施例1，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Bz-5-Larotrectinib，收率88％(70.4mmol，45.1g)。路线如下：
Figure PCTCN2019106690-appb-000023
实施例3
特戊酰氯酯化，制备I-Piv-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加饱和碳酸氢钠溶液(23g)和特戊酰氯(80mmol，9.64g)，混合物室温搅拌反应24小时，TLC中控，反应完毕后， 混合物倒入水中，分出有机层，1N氢氧化钠(100mL)洗涤,饱和食盐水(100mL)洗涤，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用甲醇-异丙醚(7：3，150mL)结晶，得到产物白色固体I-Piv-2-Larotrectinib，收率85％(68mmol，42.2g)。路线如下：
Figure PCTCN2019106690-appb-000024
实施例4
特戊酰氯酯化，制备I-Piv-5-Larotrectinib
制备方法同实施例3，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Piv-5-Larotrectinib，收率85％(70.4mmol，42.2g)。路线如下：
Figure PCTCN2019106690-appb-000025
实施例5
乙酰氯酯化，制备I-Ac-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加三乙胺(240mmol,24.2g)，和乙酰氯(80mmol，6.28g)，混合物室温搅拌反应3小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，饱和氯化铵溶液(100mL)洗涤，饱和碳酸氢钠洗涤，水洗涤，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用丙酮-石油醚(5：2，110mL)结晶，得到产物白色固体I-Ac-2-Larotrectinib，收率96.9％(77.52mmol， 44.83g)。
Figure PCTCN2019106690-appb-000026
实施例6
乙酰氯酯化，制备I-Ac-5-Larotrectinib
制备方法同实施例5，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Ac-5-Larotrectinib，收率96.5％(77.2mmol，44.7g)。路线如下：
Figure PCTCN2019106690-appb-000027
实施例7
三氟乙酸酐酯化，制备I-Tf-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加2，4，6-三甲基吡啶(240mmol，29.1g)做碱、三氟乙酸酐(80mmol，16.8g)，混合物室温搅拌反应8小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，5％稀盐酸溶液(100mL)洗涤，饱和食盐水(100mL)洗涤，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用醋酸异丙酯-石油醚(6：1，120mL)结晶，得到产物白色固体I-Tf-2-Larotrectinib，收率94％(75.2mmol，59.44g)。路线如下：
Figure PCTCN2019106690-appb-000028
实施例8
三氟乙酸酐酯化，制备I-Tf-5-Larotrectinib
制备方法同实施例7，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Tf-5-Larotrectinib，收率94％(75.2mmol，59.4g)。路线如下：
Figure PCTCN2019106690-appb-000029
实施例9
二氯乙酰氯酯化，制备I-DCAc-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加吡啶(240mmol,19.0g)，和二氯乙酰氯(80mmol，11.79g)，混合物室温搅拌反应2小时小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，饱和氯化铵溶液(100mL)洗涤，饱和碳酸氢钠洗涤，水洗涤，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用丙酮-石油醚(5：2，110mL)结晶，得到产物白色固体I-DCAc-2-Larotrectinib，收率91.6％(73.28mmol，47.43g)。路线如下：
Figure PCTCN2019106690-appb-000030
实施例10
二氯乙酰氯酯化，制备I-DCAc-5-Larotrectinib
制备方法同实施例9，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-DCAc-5-Larotrectinib，收率91％(73mmol，47g)。路线如下：
Figure PCTCN2019106690-appb-000031
实施例11
氯甲酸甲酯酯化，制备I-Moc-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加吡啶(240mmol,19.0g)，和氯甲酸甲酯(80mmol,47.2g)，混合物室温搅拌反应8小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，水洗2次，每次100mL，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用乙酸乙酯-石油醚(6：1，140mL)结晶，得到产物白色固体I-Moc-2-Larotrectinib，收率96.5％(77.2mmol，45.88g)。
Figure PCTCN2019106690-appb-000032
实施例12
氯甲酸甲酯酯化，制备I-Moc-5-Larotrectinib
制备方法同实施例11，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Moc-5-Larotrectinib，收率91％(73mmol，47g)。路线如下：
Figure PCTCN2019106690-appb-000033
实施例13
氯甲酸乙酯酯化，制备I-Eoc-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加N,N-二异丙基乙胺(240mmol,30.48g)和氯甲酸乙酯(80mmol,8.68g)，混合物室温搅拌反应6小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，5％稀盐酸溶液(100mL)洗涤，饱和食盐水(100mL)洗涤，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用醋酸异丙酯-石油醚(6：1，120mL)结晶，得到产物白色固体I-Eoc-2-Larotrectinib，收率94.3％(75.44mmol，45.89g)。路线如下：
Figure PCTCN2019106690-appb-000034
实施例14
氯甲酸乙酯酯化，制备I-Eoc-5-Larotrectinib
制备方法同实施例13，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Eoc-5-Larotrectinib，收率94％(75mmol，75g)。路线如下：
Figure PCTCN2019106690-appb-000035
实施例15
Boc酸酐酯化，制备I-Boc-2-Larotrectinib
在2000毫升反应瓶中，加入氯仿400mL，化合物I-2-Larotrectinib(80mmol，42.9g)，室温搅拌至溶解后，同时添加DMAP(4mmol,0.5g)，KOH(240mmol,13.44g),Boc酸酐(80mmol,17.46g)，混合物室温搅拌反应16小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，5％稀盐酸溶液(100mL)洗涤，饱和食盐水(100mL)洗涤，无水硫酸镁干燥，减压浓缩去溶剂，剩余物用醋酸异丙酯-石油醚(6：1，120mL)结晶，得到产物白色固体I-Boc-2-Larotrectinib，收率94％(75.2mmol，47.86g)。路线如下：
Figure PCTCN2019106690-appb-000036
实施例16
Boc酸酐酯化，制备I-Boc-5-Larotrectinib
制备方法同实施例15，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Boc-5-Larotrectinib，收率94％(75mmol，47g)。
实施例17
氯甲酸-2,2,2-三氯乙酯(Troc)酯化，制备I-Troc-2-Larotrectinib，路线如下：
Figure PCTCN2019106690-appb-000037
在500毫升反应瓶中，加入DCM 150mL，化合物I-2-Larotrectinib(80mmol，42.91g)和吡啶＝79(2.5eq,200mmol,15.80g,)，室温搅拌5分钟，滴加氯甲酸-2,2,2-三氯乙酯(C3H2Cl4O2＝211.85,1.2eq,96mmol,13.66g,20.34mmol)溶解于DCM(30ml)的溶液，室温搅拌3小时，TLC中控，反应完毕后，混合物倒入水中，分出有机层，3％HCl洗涤，饱和碳酸氢钠洗涤，食盐水(80gx3)洗涤三次，有机相干燥经过无水硫酸钠干燥，抽滤，滤液浓缩至粘稠状，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物白色固体I-Troc-2-Larotrectinib(收率91.2％,51.93g)。
实施例18
氯甲酸-2,2,2-三氯乙酯(Troc)酯化，制备I-Troc-5-Larotrectinib
制备方法同实施例17，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Boc-5-Larotrectinib，收率91％(72.8mmol，51g)。
实施例19
三甲基硅乙氧羰基氯(Teoc)酯化，制备I-Teoc-2-Larotrectinib
Figure PCTCN2019106690-appb-000038
在500毫升反应瓶中，加入二氯甲烷150mL，化合物I-2-Larotrectinib(80mmol，42.91g)和吡啶＝79(2.5eq,200mmol,15.80g,)，降低温度至0-5度，缓慢滴加三甲基硅乙氧羰基氯(Teoc)(C 6H 13ClO 2Si＝180.70,2.0eq,28.91g, 160mmol)溶解于DCM(30ml)的溶液，滴加完毕，室温下继续搅拌3小时，TLC中控，反应完毕后，加入甲醇5mL,室温下搅拌反应半小时，混合物倒入水中，分出有机层，3％HCl洗涤，饱和碳酸氢钠洗涤，食盐水(80gx3)洗涤三次，有机相干燥经过无水硫酸钠干燥，抽滤，滤液浓缩至粘稠状，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物白色固体I-Teoc-2-Larotrectinib(收率83.6％,45.52g)。
实施例20
三甲基硅乙氧羰基氯(Teoc)酯化，制备I-Teoc-5-Larotrectinib
制备方法同实施例19，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Teoc-5-Larotrectinib，收率83％(66.4mmol，45g)。
实施例21
叔丁基二甲基氯硅烷醚化，制备I-TBS-2-Larotrectinib
Figure PCTCN2019106690-appb-000039
在500毫升反应瓶中，加入DMF 150mL，冷却至零度，依次加入化合物I-2-Larotrectinib(80mmol，42.91g)，叔丁基二甲基氯硅烷(TBS-Cl，C 6H 15ClSi＝150.72)(1.3eq，104mml,15.67g),和咪唑(C 3H 4N 2＝68.08，1.5eq，120mmol,8.17g)，混合物室温下搅拌反应至转化完全(TLC跟踪)通常过夜，混合物以等体积氯仿稀释，水洗涤三次，盐水洗涤1次。有机层干燥，减压浓缩，剩余物硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-TBS-2-Larotrectinib(86.8％,45.17g)
实施例22
叔丁基二甲基氯硅烷醚化，制备I-TBS-5-Larotrectinib
制备方法同实施例21，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-TBS-5-Larotrectinib，收率86％(68.8mmol，45g)。
实施例23
三异丙基氯甲硅烷醚化，制备I-TIPS-2-Larotrectinib
Figure PCTCN2019106690-appb-000040
在500毫升反应瓶中，加入DMF 150mL，冷却至零度，依次加入化合物I-2-Larotrectinib(80mmol，42.91g)，三异丙基氯甲硅烷(TIPSCl，C9H21ClSi＝192.8,1.3eq,104mmol,20.05g)，和咪唑(C3H4N2＝68.08，1.3eq，104mmol,7.07g)，混合物室温下搅拌反应至转化完全(TLC跟踪)通常过夜，混合物以等体积氯仿稀释，水洗涤三次，盐水洗涤1次。有机层干燥，减压浓缩，剩余物硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-TIPS-2-Larotrectinib(88.8％,49.21g)。
实施例24
三异丙基氯甲硅烷醚化，制备I-TIPS-5-Larotrectinib
制备方法同实施例23，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-TIPS-5-Larotrectinib，收率88％(70.4mmol，49g)。
实施例25
叔丁基二苯基氯硅烷醚化，制备I-TBDPS-2-Larotrectinib
Figure PCTCN2019106690-appb-000041
在500毫升反应瓶中，加入THF 100mL，化合物I-2-Larotrectinib(80mmol，42.91g)，加入咪唑(2eq，160mmol,10.89g)，搅拌反应半小时后，加入叔丁基二苯基氯硅烷(TBDPSCl，1.5eq，120mmol,32.98g),混合物在25度下，搅拌 反应至完全(TLC跟踪)，混合物以300mL氯仿稀释，加入氯化铵溶液(100mL，含有37.2g氯化铵)洗涤1次，饱和碳酸氢钠洗涤2次,每次100ml，盐水(100ml)洗涤1次，有机相干燥(无水硫酸镁)，过滤，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-TBDPS-2-Larotrectinib(85.7％,53.12g)。
实施例26
叔丁基二苯基氯硅烷醚化，制备I-TBDPS-5-Larotrectinib
制备方法同实施例25，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-TBDPS-5-Larotrectinib，收率86％(68.8mmol，53g)。
实施例27
对甲氧苄基醚化PMB-(p-Methoxybenzyl)ether，制备I-PMB-2-Larotrectinib
Figure PCTCN2019106690-appb-000042
在500毫升反应瓶中，加入DMF 100mL，化合物I-2-Larotrectinib(80mmol，42.91g)溶解后的溶液，在氮气保护下，滴加到冷却至零度的钠氢(1.3eq,104mmol,2.5g)溶解在DMF(20mL)的溶液中，混合物在零度下搅拌30分钟，对甲氧苄基溴(1.3eq,104mmol,201.0g)滴加到上述溶液中，添加催化量量冠醚，反应液在室温下继续搅拌16小时，TLC跟踪至反应完成，缓慢添加甲醇淬灭反应，溶液用氯仿和水稀释，水洗3次，盐水洗涤2次，有机层用无水硫酸钠干燥，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-PMB-2-Larotrectinib(82.8％,44.15g)。
实施例28
对甲氧苄基醚化PMB-(p-Methoxybenzyl)ether，制备I-PMB-5-Larotrectinib
制备方法同实施例27，原料采用化合物I-5-Larotrectinib，得到产物白色固 体I-PMB-5-Larotrectinib，收率83％(66.4mmol，43.6g)。
实施例29
氯甲基甲醚醚化，制备I-MOM-2-Larotrectinib
Figure PCTCN2019106690-appb-000043
在500毫升反应瓶中，氮气保护下，加入无水DCM 180mL，化合物I-2-Larotrectinib(80mmol，42.91g)，无水N,N-二异丙基乙胺(2.0eq，160mmol,20.68g),反应混合物冷却至零度，加入氯甲基甲醚(MOM-Cl，1.5eq,120mmol,9.66g)，混合物升至室温，搅拌反应完全(TLC跟踪)，大约需要8小时以上，加入氯化铵溶液(100mL，含有37.2g氯化铵)洗涤1次，饱和碳酸氢钠洗涤2次,每次100ml，盐水(100ml)洗涤1次，盐水洗涤1次，有机相无水硫酸镁干燥，过滤，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)，得到产物I-MOM-2-Larotrectinib(74.4％,34.54g)。
实施例30
氯甲基甲醚醚化，制备I-MOM-5-Larotrectinib
制备方法同实施例29，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-MOM-5-Larotrectinib，收率74％(59mmol，34g)。
实施例31
甲氧基乙氧基甲基氯醚化，制备I-MEM-2-Larotrectinib
Figure PCTCN2019106690-appb-000044
在500毫升反应瓶中，加入干燥的DCM 180mL，化合物I-2-Larotrectinib(0.8mmol)，甲氧基乙氧基甲基氯(MEM-Cl，1.5eq,120mmol,14.95g)，加入N,N-二异丙基乙胺(1.5eq，120mmol,15.51g),反应混合物室温搅拌反应完全(TLC跟踪)，大约需要5小时，反应混合物加入DCM(180mL)稀释，混合物水洗涤2次,每次100mL，盐水(100mL)洗涤1次，有机相干燥(无水硫酸钠)，过滤，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-MEM-2-Larotrectinib(76.8％,38.37g)。
实施例32
甲氧基乙氧基甲基氯醚化，制备I-MEM-5-Larotrectinib
制备方法同实施例30，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-MEM-5-Larotrectinib，收率76％(60.8mmol，38g)。
实施例33
2-(三甲基硅烷基)乙氧甲基氯醚化，制备I-SEM-2-Larotrectinib
Figure PCTCN2019106690-appb-000045
在500毫升反应瓶中，加入DCM180mL，化合物I-2-Larotrectinib(80mmol，42.91g)，N,N-二异丙基乙胺(320mmol,41.36g),反应混合物在25度下，加入2-(三甲基硅烷基)乙氧甲基氯(SEM-Cl，240mmol,40.01g)，混合物在25度下，搅拌反应至完全(TLC跟踪)，加入氯化铵溶液(100mL，含有37.2g氯化铵)洗涤1次，饱和碳酸氢钠洗涤2次,每次100ml，盐水(100ml)洗涤1次，有机相无水硫酸镁干燥，过滤，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)，得到产物I-SEM-2-Larotrectinib(86.8％,46.28g)。
实施例34
2-(三甲基硅烷基)乙氧甲基氯醚化，制备I-SEM-5-Larotrectinib，
制备方法同实施例33，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-SEM-5-Larotrectinib，收率86％(68.8mmol，46g)。
实施例35
四氢吡喃醚化，制备I-THP-2-Larotrectinib
Figure PCTCN2019106690-appb-000046
在500毫升反应瓶中，加入DCM 150mL，化合物I-2-Larotrectinib(80mmol，42.91g)和对甲苯磺酸吡啶盐(0.40g,1.56mmol)，搅拌5分钟，滴加3,4-二氢-2H-吡喃(13.66g,168.46mmol)溶解于DCM(50ml)的溶液，室温搅拌过夜，食盐水(80gx3)洗涤三次，有机相干燥经过无水硫酸钠干燥，抽滤，滤液浓缩至粘稠状，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-THP-2-Larotrectinib(98.6％,48.94g)。
实施例36
四氢吡喃醚化，制备I-THP-5-Larotrectinib，
制备方法同实施例35，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-THP-5-Larotrectinib，收率98％(78.4mmol，48g)。
实施例37
1-乙氧基乙醇乙酸酯(EE)醚化，制备I-EE-2-Larotrectinib
Figure PCTCN2019106690-appb-000047
在500毫升反应瓶中，加入DCM 150mL，化合物I-2-Larotrectinib(80mmol，42.91g),对甲苯磺酸吡啶盐(0.40g,1.56mmol)，和1-乙氧基乙醇乙酸酯(C6H12O3＝132.16，1.5eq，120mmol，15.86g)，室温搅拌1.5h，食盐水(80gx3)洗涤三次，有机相经过无水硫酸钠干燥，抽滤，滤液浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-EE-2-Larotrectinib(85.7％,41.72g)。
实施例38
1-乙氧基乙醇乙酸酯(EE)醚化，制备I-EE-5-Larotrectinib，
制备方法同实施例37，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-EE-5-Larotrectinib，收率85％(68mmol，41g)。
实施例39
烯丙基磺酰氯醚化，制备I-Als-2-Larotrectinib
Figure PCTCN2019106690-appb-000048
在500毫升反应瓶中，加入DCM 180mL，化合物I-2-Larotrectinib(80mmol，42.91g)，冷却至-30度，加入烯丙基磺酰氯Als(C3H5ClO2S＝140.58,2.5eq，200mmol,28.12g),在此温度下反应2小时后，反应混合物升至室温搅拌反应完全(TLC跟踪)，大约需要6小时，反应混合物减压浓缩，剩余物溶解在乙酸乙酯(120mL)中，混合物饱和碳酸氢钠溶液洗涤2次，每次(80mL)，盐水(80mL)洗涤1次，有机相干燥(无水硫酸钠)，过滤，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-Als-2-Larotrectinib(86％,44.06g)。
实施例40
烯丙基磺酰氯醚化，制备I-Als-5-Larotrectinib，
制备方法同实施例39，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-Als-5-Larotrectinib，收率86％(68.8mmol，44g)。
实施例41
对甲氧基苯酚醚化PMP-(p-Methoxyphenyl)ether，制备I-PMP-2-Larotrectinib
Figure PCTCN2019106690-appb-000049
在500毫升反应瓶中，加入THF 100mL，化合物I-2-Larotrectinib(80mmol，42.91g)，三苯基磷(1.3eq,104mmol,31.65g),偶氮二甲酸二乙酯(1.3eq,104mmol,18.11g)，对甲氧基苯酚(3eq,240mmol,29.79g)，反应混合物加热至80度，搅拌反应至完全(TLC跟踪)，大约需要2小时，混合物减压浓缩，剩余物经过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到产物I-PMP-2-Larotrectinib(81.3％,41.6g)。
实施例42
对甲氧基苯酚醚化PMP-(p-Methoxyphenyl)ether，制备I-PMP-5-Larotrectinib
制备方法同实施例41，原料采用化合物I-5-Larotrectinib，得到产物白色固体I-PMP-5-Larotrectinib，收率81％(64.8mmol，43.6g)。
步骤二：标记前体的制备
实施例43
制备标记前体I(III)-SPIAd-Bz-2-Larotrectinib
Figure PCTCN2019106690-appb-000050
Figure PCTCN2019106690-appb-000051
在10mL反应瓶中加入三氟乙酸0.39mL，氯仿0.13mL，搅拌下，向混合溶液中加入脲-过氧化氢复合物(CO(NH 2) 2·H 2O 2＝94.07,1.36g,14.5mmol),I-Bz-2-Larotrectinib(70.45mg，0.11mmol)，混合物室温搅拌60min，真空浓缩去溶剂，向剩余物中加入乙醇0.8mL，然后加入含有SPIAd(25.3mg，0.11mmol)的10％碳酸钠溶液(0.5mL)，并再用10％碳酸钠溶液(0.3mL)调节pH值至9，混合物室温搅拌反应70min，然后加入5mL水稀释，以DCM萃取三次，每次5mL，合并有机层，无水硫酸镁干燥，真空浓缩，剩余物硅胶柱层析(含有0-10％甲醇的乙酸乙酯溶液洗涤)得到标记前体I(III)-SPIAd-Bz-2-Larotrectinib白色固体(18.32mg，19％得率)。
实施例44
类似实施例43的方法制备I(III)-SPIAd-Bz-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Bz-5-Larotrectinib，收率19％(18mmol，18mg)。
实施例45
制备标记前体I(III)-SPIAd-Piv-2-Larotrectinib
Figure PCTCN2019106690-appb-000052
Figure PCTCN2019106690-appb-000053
在10mL圆底烧瓶中，添加三氟乙酸酐(C 4F 6O 3＝210.04，1.511C g/mL,0.068mL,0.489mmol，102.75mg),三氟乙酸(CF 3COOH＝114.02，1.5351g/cm 3,0.18mL,0.276g,2.43mmol),搅拌下，慢慢添加脲-过氧化氢(1.125mmol,106mg)反应放热，控制体系温度低于30℃，加完后，再加入I-Piv-2-Larotrectinib(155.12mg，0.25mmol)，反应混合物冰水浴冷却至零度左右，随后缓慢添加无水硫酸钠(41mg,0.5mmol)，加完后,反应混合物升温至40℃反应1-6小时，TLC检测原料I-Piv-2-Larotrectinib反应完毕，然后加水2.5mL稀释，DCM萃取三次，每次5mL，合并有机相，无水硫酸镁干燥，过滤减压浓缩，剩余物硅胶柱层析(0-10％甲醇的乙酸乙酯溶液洗脱)，得到中间体I-Piv-TfAc-2-Larotrectinib白色固体(143.91mg，68％得率)。
在10mL圆底烧瓶中，添加Na 2CO 3(98.58mg,0.93mmol),MeCN(0.52ml),SPIAd(39.1mg,0.17mmol)，非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物成乳白色悬浮液。中间体I-Piv-TfAc-2-Larotrectinib(143.91mg，0.17mmol)一次性加入到上述激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成浓稠的奶油混合物。添加水10mL,混合物再搅拌1分钟，过滤除去米黄色双相溶液中蓬松的白色悬浮物，滤饼水洗涤2次，每次5mL,每次洗涤时均需要将水抽干，滤饼再用乙醚(10mL)洗涤1次，高真空干燥得到标记前体物I(III)-SPIAd-Piv-2-Larotrectinib类白色固体(113.33mg,78％,2步总收率53％),m.p.100度(分解)。
实施例46
类似实施例45的方法制备I(III)-SPIAd-Piv-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Piv-5-Larotrectinib，收率78％(113mg，2步总收率53％)。
实施例47
制备标记前体I(III)-SPIAd-Ac-2-Larotrectinib
Figure PCTCN2019106690-appb-000054
在2mL圆底烧瓶中，添加三氟乙酸酐(0.068mL,0.489mmol，102.75mg),三氟乙酸(0.18mL,0.276g,2.43mmol),氯仿0.18mL,搅拌下，慢慢添加Oxone(136.36mg,0.225mmol)，加完后，再加入I-Ac-2-Larotrectinib(127.25mg，0.22mmol)，反应混合物冰水浴冷却至零度左右，随后缓慢添加无水硫酸镁(60mg,0.5mmol)，加完后,反应混合物室温25℃下反应6小时，TLC检测原料I-Ac-2-Larotrectinib反应完毕，将反应物转入3mL冰水中稀释，DCM萃取三次，每次5mL，合并有机相，食盐水洗涤3次，每次2mL，有机相无水硫酸镁干燥，过滤减压浓缩，剩余物硅胶柱层析(0-10％甲醇的乙酸乙酯溶液洗脱)，得到中间体I-Ac-TfAc-2-Larotrectinib浅黄色固体(114.68mg，0.143mmol,64.8％得率)。
在2mL圆底烧瓶中，添加NaHCO 3(78.12mg,0.93mmol),丙酮(0.52ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物成乳白色悬浮液。中间体I-Ac-TfAc-2-Larotrectinib(143.91mg，0.17mmol)一次性加入到上述激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成黄色，TLC跟踪直到原料转化完毕，滤去不溶物，反应瓶用二氯甲烷洗涤三次，每次0.12mL，洗涤液体淋洗不溶物，收集二氯甲烷黄色液体。减压浓缩(20度下)蒸干二氯甲烷，再高真空度下抽干1小时，得到标记前体物I(III)-SPIAd-Ac-2-Larotrectinib黄色固体(138.15mg,收率46.6％)。
实施例48
类似实施例47的方法制备I(III)-SPIAd-Ac-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Ac-5-Larotrectinib，收率46％(138mg)。
实施例49
制备标记前体I(III)-SPIAd-Tf-2-Larotrectinib
Figure PCTCN2019106690-appb-000055
在2mL圆底烧瓶中，添加三氟乙酸酐(0.068mL,0.489mmol，102.75mg),三氟乙酸(0.18mL,0.276g,2.43mmol),氯仿0.18mL,搅拌下，慢慢添加Oxone(136.36mg,0.225mmol)，加完后，再加入I-Tf-2-Larotrectinib(139.12mg，0.22mmol)，反应混合物冰水浴冷却至零度左右，随后缓慢添加无水硫酸镁(60mg,0.5mmol)，加完后,反应混合物室温25℃下反应6小时，TLC检测原料I-Tf-2-Larotrectinib反应完毕，将反应物转入3mL冰水中稀释，DCM萃取三次，每次5mL，合并有机相，食盐水洗涤3次，每次2mL，有机相无水硫酸镁干燥，过滤减压浓缩，剩余物硅胶柱层析(0-10％甲醇的乙酸乙酯溶液洗脱)，得到中间体I-Tf-TfAc-2-Larotrectinib浅黄色固体(117.46mg，0.137mmol,62.2％得率)。
在2mL圆底烧瓶中，添加K2CO3(128.34mg,0.93mmol),甲醇(0.52ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物成乳白色悬浮液。中间体I-Tf-TfAc-2-Larotrectinib(117.46mg，0.137mmol)一次性加入到上述激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应 混合物逐渐变成黄色，TLC跟踪直到原料转化完毕，滤去不溶物，反应瓶用二氯甲烷洗涤三次，每次0.12mL，洗涤液体淋洗不溶物，收集二氯甲烷黄色液体。减压浓缩(20度下)蒸干二氯甲烷，再高真空度下抽干1小时，得到标记前体物I(III)-SPIAd-Tf-2-Larotrectinib黄色固体(53.9mg,收率45.4％)。
实施例50
类似实施例49的方法制备I(III)-SPIAd-Tf-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Tf-5-Larotrectinib，收率46％(54mg)。
实施例51
制备标记前体I(III)-SPIAd-CAc-2-Larotrectinib
Figure PCTCN2019106690-appb-000056
在2mL反应器中,搅拌下，添加三氟乙酸0.3mL、三氟乙酸酐(0.9mL)、Oxone(H 3K 5O 18S 4＝614.76，101.44mg，0.165mmol),氯仿0.13mL，室温下激烈搅拌均匀，加入I-CAc-2-Larotrectinib(67.41mg，0.11mmol)，产生的混合物冷却至零度，无水醋酸钠(0.53g,6.45mmol)缓慢添加到激烈搅拌的混合物中，加完，混合物加热到40度，激烈搅拌反应2小时，TLC跟踪直到原料转化完毕，混合物冷却到室温，转入2mL水中稀释，二氯甲烷萃取3次，每次3毫升，合并萃取有机相，饱和食盐水洗涤3次，每次3mL,无水硫酸钠干燥，过滤，浓缩，剩余物用正庚烷/乙酸乙酯洗涤，过滤的得到黄色固体I-CAc-TfAc-2-Larotrectinib(57.12mg,0.068mmol,61.9％yield)。
在2mL反应器中，添加KHCO3(93mg,0.93mmol),乙醇(0.52ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物成乳白色悬浮液。中间体I-CAc-TfAc-2-Larotrectinib(57.12mg,0.068mmol)一次性加入到上述激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成黄色，TLC跟踪直到原料转化完毕，滤去不溶物，反应瓶用二氯甲烷洗涤三次，每次0.12mL，洗涤液体淋洗不溶物，收集二氯甲烷黄色液体。减压浓缩(20度下)蒸干二氯甲烷，再高真空度下抽干1小时，得到标记前体物I(III)-SPIAd-CAc-2-Larotrectinib黄色固体(26.84mg,收率46.6％)。
实施例52
类似实施例51的方法制备I(III)-SPIAd-CAc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-CAc-5-Larotrectinib，收率46％(27mg)。
实施例53
制备标记前体I(III)-SPIAd-DCAc-2-Larotrectinib
Figure PCTCN2019106690-appb-000057
在2mL反应器中,搅拌下，添加三氟乙酸0.3mL、三氟乙酸酐(0.9mL)、Oxone(H 3K 5O 18S 4＝614.76，101.44mg，0.165mmol),氯仿0.13mL，室温下激烈搅拌均匀，加入I-DCAc-2-Larotrectinib(71.2mg，0.11mmol)，产生的混合物冷却至零度，无水醋酸钠(0.53g,6.45mmol)缓慢添加到激烈搅拌的混合物中，加完，混合物加热到40度，激烈搅拌反应2小时，TLC跟踪直到原料转化完毕，混合物冷却到室温，转入2mL水中稀释，二氯甲烷萃取3次，每次3毫升， 合并萃取有机相，饱和食盐水洗涤3次，每次3mL,无水硫酸钠干燥，过滤，浓缩，剩余物用正庚烷乙酸乙酯洗涤，过滤的得到黄色固体I-DCAc-TfAc-2-Larotrectinib(65.32mg,0.075mmol,68％yield)。
在2mL反应瓶中，加入含有辅助酸金刚烷(SPI-Adaman(0.1mmol,23mg)的10％碳酸钠水溶液(w/v.0.75mL,0.33M)，加入乙醇(1mL),随后迅速加入I-DCAc-TfAc-2-Larotrectinib(0.096mmol,84.53mg)，反应混合物室温下，激烈搅拌反应0.5h,TLC跟踪反应至原料转化完全，反应混合物转入2mL水中稀释，二氯甲烷萃取三次，每次3mL，合并有机萃取相，无水硫酸钠干燥，过滤，减压浓缩，剩余物经过硅胶柱层析，用正庚烷/乙酸乙酯＝10/1洗脱，得到标记前体I(III)-SPIAd-DCAc-2-Larotrectinib白色固体(43.16mg,收率46.8％,2步总收率46.8％)。
实施例54
类似实施例53的方法制备I(III)-SPIAd-DCAc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-DCAc-5-Larotrectinib(43mg,收率47％,2步总收率46.8％)。
实施例55
制备标记前体I(III)-SPIAd-Moc-2-Larotrectinib
Figure PCTCN2019106690-appb-000058
在2mL反应器中,添加三氟乙酸0.36mL、氯仿0.18mL,搅拌下，添加I-Moc-2-Larotrectinib(89.16mg，0.15mmol)、Oxone(110.66mg,0.18mmol)，混合 物升温至45度搅拌反应3小时，然后减压浓缩去溶剂，剩余物中添加乙醇1.2mL,SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠溶液0.68mL,并用10％碳酸钠溶液调节pH12。混合物50度搅拌3小时，TLC跟踪反应至原料转化完全，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)，得到标记前体I(III)-SPIAd-Moc-2-Larotrectinib白色固体(38.91mg,得率31.3％)。
实施例56
类似实施例55的方法制备I(III)-SPIAd-Moc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Moc-5-Larotrectinib，收率31％(39mg)。
实施例57
制备标记前体I(III)-SPIAd-Eoc-2-Larotrectinib
Figure PCTCN2019106690-appb-000059
在2mL反应器中,添加三氟乙酸0.36mL、氯仿0.18mL,搅拌下，添加I-Eoc-2-Larotrectinib(91.26mg，0.15mmol)、Oxone(110.66mg,0.18mmol)，混合物升温至37度搅拌反应3小时，然后减压浓缩去溶剂，剩余物中添加乙醇1.2mL,SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠溶液0.68mL,并用10％碳酸钠溶液调节pH11。混合物室温60度搅拌2小时，TLC跟踪反应至原料转化完全，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)， 得到标记前体I(III)-SPIAd-Eoc-2-Larotrectinib白色固体(33.57mg,得率33.2％)。
实施例58
类似实施例57的方法制备I(III)-SPIAd-Eoc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Eoc-5-Larotrectinib，收率33％(34mg)。
实施例59
制备标记前体I(III)-SPIAd-Boc-2-Larotrectinib
Figure PCTCN2019106690-appb-000060
在2mL反应器中,加入二氯甲烷0.8mL,搅拌下，添加I-Boc-2-Larotrectinib(89.11mg，0.14mmol)、mCPBA(40mg,0.18mmol)，混合物室温激烈搅拌反应1-2h，TLC跟踪直到原料转化完毕，待用。
在2mL反应器中，加入KOH＝56.1(47.12mg,0.84mmol),二氯甲烷(0.47ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物呈现乳白色悬浮液,溶液酸碱度pH12。将上述待用物料一次性转入到激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成黄色，TLC跟踪直到原料转化完毕，滤去不溶物，反应瓶用二氯甲烷洗涤三次，每次0.12mL，洗涤液体淋洗不溶物，收集二氯甲烷黄色液体。减压浓缩(20度下)蒸干二氯甲烷，再高真空度下抽干1小时，得到标记前体物I(III)-SPIAd-Boc-2-Larotrectinib黄色固体(49.74mg,收率40.8％),m.p.88.6度(分解)。
实施例60
类似实施例59的方法制备I(III)-SPIAd-Boc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Boc-5-Larotrectinib，收率40％(49mg)。
实施例61
制备标记前体I(III)-SPIAd-Troc-2-Larotrectinib
Figure PCTCN2019106690-appb-000061
在2mL反应器中,添加三氟乙酸0.36mL、氯仿0.18mL,搅拌下，添加I-Troc-2-Larotrectinib(106.76mg，0.15mmol)、Oxone(110.66mg,0.18mmol)，混合物升温至70度搅拌反应2小时，然后减压浓缩去溶剂，剩余物中添加乙醇1.2mL,SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠溶液0.68mL,并用10％碳酸钠溶液调节pH9。混合物室温搅拌70分钟，TLC跟踪反应至原料转化完全，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)，得到标记前体I(III)-SPIAd-Troc-2-Larotrectinib白色固体(53.92mg,得率38％)。
实施例62
类似实施例61的方法制备I(III)-SPIAd-Troc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Troc-5-Larotrectinib，收率38％(53mg)。
实施例63
制备标记前体I(III)-SPIAd-Teoc-2-Larotrectinib
Figure PCTCN2019106690-appb-000062
Figure PCTCN2019106690-appb-000063
在2mL圆底烧瓶中，添加三氟乙酸酐(0.068mL,0.489mmol，102.75mg),三氟乙酸(0.18mL,0.276g,2.43mmol),氯仿0.18mL,搅拌下，慢慢添加Oxone(136.36mg,0.225mmol)，加完后，再加入I-Teoc-2-Larotrectinib(147.73mg，0.22mmol)，反应混合物冰水浴冷却至零度左右，随后缓慢添加无水硫酸镁(60mg,0.5mmol)，加完后,反应混合物室温25度下反应6小时，TLC检测原料I-Teoc-2-Larotrectinib反应完毕，将反应物转入3mL冰水中稀释，DCM萃取三次，每次5mL，合并有机相，食盐水洗涤3次，每次2mL，有机相无水硫酸镁干燥，过滤减压浓缩，剩余物硅胶柱层析(0-10％甲醇的乙酸乙酯溶液洗脱)，得到中间体I-teoc-TfAc-2-Larotrectinib浅黄色固体(153.96mg，0.173mmol,78.4％得率)。
在10mL圆底烧瓶中，添加KOH(52.08mg,0.93mmol),MeCN(0.52ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物成乳白色悬浮液。中间体I-Teoc-TfAc-2-Larotrectinib(143.91mg，0.17mmol)一次性加入到上述激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成浓稠的奶油混合物。添加水10mL,混合物再搅拌1分钟，过滤除去米黄色双相溶液中蓬松的白色悬浮物，滤饼水洗涤2次，每次5mL,每次洗涤时均需要将水抽干，滤饼再用乙醚(10mL)洗涤1次，高真空干燥得到标记前体物I(III)-SPIAd-Teoc-2-Larotrectinib类白色固体(121.31mg,78％,2步总收率61.1％),m.p.115度(分解)。
实施例64
类似实施例63的方法制备I(III)-SPIAd-Teoc-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Teoc-5-Larotrectinib(121mg,78％，2步总收率61％)。
实施例65
制备标记前体I(III)-SPIAd-TBS-2-Larotrectinib
Figure PCTCN2019106690-appb-000064
在10mL反应器中,添加三氟乙酸0.39mL、乙腈0.13mL,搅拌下，混合物冷却至零度，添加Oxone(100mg,0.165mmol)，添加I-TBS-2-Larotrectinib(70.2mg，0.11mmol)，混合物零度搅拌反应30分钟，剩余物中添加乙醇0.8mL，SPIAd(25.3mg,0.11mmol)溶解于10％碳酸钠溶液0.5mL，并用10％碳酸钠溶液0.3mL调节pH9。混合物室温搅拌70分钟，然后加水5mL稀释，DCM萃取三次，每次5mL，合并有机相，硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-10％甲醇的乙酸乙酯溶液洗脱)，得到标记前体I(III)-SPIAd-TBS-2-Larotrectinib白色固体(17.52mg,得率18％)。
实施例66
类似实施例65的方法制备I(III)-SPIAd-TBS-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-TBS-5-Larotrectinib(38mg,30％)。
实施例67
制备标记前体I(III)-SPIAd-TBS-2-Larotrectinib的另一种方法
Figure PCTCN2019106690-appb-000065
在2mL反应器中,加入二氯甲烷0.8mL,搅拌下，添加I-TBS-2-Larotrectinib(89.11mg，0.14mmol)、mCPBA(40mg,0.18mmol)，混合物室温激烈搅拌反应1-2h，TLC跟踪直到原料转化完毕，待用。
在2mL反应器中，加入KOH＝56.1(47.12mg,0.84mmol),二氯甲烷(0.47ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物呈现乳白色悬浮液,溶液酸碱度pH12。将上述待用物料一次性转入到激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成黄色，TLC跟踪直到原料转化完毕，滤去不溶物，反应瓶用二氯甲烷洗涤三次，每次0.12mL，洗涤液体淋洗不溶物，收集二氯甲烷黄色液体。减压浓缩(20度下)蒸干二氯甲烷，再高真空度下抽干1小时，得到标记前体物I(III)-SPIAd-TBS-2-Larotrectinib黄色固体(38.16mg,总收率30.8％)。
实施例68
类似实施例67的方法制备I(III)-SPIAd-TBS-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-TBS-5-Larotrectinib(38mg,30％)。
实施例69
制备标记前体I(III)-SPIAd-TBDPS-2-Larotrectinib
Figure PCTCN2019106690-appb-000066
在2mL反应器中,添加三氟乙酸0.53mL、氯仿0.18mL,氯化镁(MgCl 2，0.95mg,0.01mmol)搅拌下，添加I-TBDPS-2-Larotrectinib(116.22mg，0.15mmol),Oxone(H 3K 5O 18S 4＝614.76，136.36mg,0.225mmol)，混合物升温至80℃，搅拌反应3小时，TLC跟踪至原料反应完全，过滤除固体，然后减压浓缩去溶剂，剩余物中添加乙醇1.2mL,SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠溶液0.68mL,并用10％碳酸钠溶液0.41mL调节pH9。混合物室温搅拌70分钟，TLC跟踪反应完成，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，无水硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)，得到标记前体I(III)-SPIAd-PMP-2-Larotrectinib白色固体(52.97mg,得率35％)。
实施例70
类似实施例69的方法制备I(III)-SPIAd-TBS-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-TBS-5-Larotrectinib(53mg,35％)。
实施例71
制备标记前体I(III)-SPIAd-TIPS-2-Larotrectinib
Figure PCTCN2019106690-appb-000067
在2mL反应器中,二氯甲烷4mL，搅拌下，添加三氟乙酸酐(0.16mL，0.24g,1.14mmol)、Oxone(67.63mg，0.11mmol),2,2,6,6-四甲基哌啶-氧化物(TEMPO，0.00 1mmol,0.056mg)、无水氯化锂(LiCl,0.42mg,0.01mmol)，室温下搅拌均匀， 加入I-TIPS-2-Larotrectinib(86.33mg，0.11mmol)，产生的混合物室温反应2小时，TLC跟踪反应过程，原料消失后，过滤去除固体物，浓缩有机相后，剩余物硅胶柱层析分离(展开剂：0-50％乙酸乙酯-正庚烷，v/v,洗脱)，收集目标产物洗脱液，浓缩得到无色固体I-TIPS-TfAc-2-Larotrectinib(63.67mg,0.069mmol,63％yield)，
在2mL反应瓶中，加入含有辅助酸金刚烷(SPI-Adaman(0.1mmol,23mg)的10％碳酸钠水溶液(w/v.0.75mL,0.33M)，加入乙醇(1mL),随后迅速加入I-TIPS-TfAc-2-Larotrectinib(0.069mmol,63.67mg)，反应混合物室温下，激烈搅拌反应4h,TLC跟踪反应至原料转化完全，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，剩余物经过硅胶柱层析(展开剂：0-50％乙酸乙酯-石油醚，v/v,洗脱)，收集目标产物洗脱液，浓缩得到标记前体I(III)-SPIAd-TIPS-2-Larotrectinib白色固体(42.82mg,2步总收率42％)。
实施例72
类似实施例71的方法制备I(III)-SPIAd-TIPS-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-TIPS-5-Larotrectinib(42mg，2步总收率42％)。
实施例73
制备标记前体I(III)-SPIAd-PMB-2-Larotrectinib
Figure PCTCN2019106690-appb-000068
在2mL反应器中,添加三氟乙酸0.53mL、氯仿0.18mL,搅拌下，添加I-PMB-2-Larotrectinib(98.47mg，0.15mmol)，氯化钠(0.59mg,0.01mmol), Oxone(H 3K 5O 18S 4＝614.76，138.32mg,0.225mmol)，混合物升温至80℃，搅拌反应3小时，TLC跟踪至原料反应完全，然后减压浓缩去溶剂，剩余物中添加乙醇1.2mL,SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠溶液0.68mL,并用10％碳酸钠溶液调节pH9。混合物室温搅拌70分钟，TLC跟踪反应完成，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，无水硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)，得到标记前体I(III)-SPIAd-PMB-2-Larotrectinib黄色固体(44.89mg,得率33.6％)。
实施例74
类似实施例73的方法制备I(III)-SPIAd-PMB-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-PMB-5-Larotrectinib(45mg,34％)。
实施例75
制备标记前体I(III)-SPIAd-MOM-2-Larotrectinib
Figure PCTCN2019106690-appb-000069
在2mL反应器中,乙腈0.4mL，搅拌下，添加Oxone(H 3K 5O 18S 4＝614.76，67.63mg，0.11mmol),丙酮0.05mL,室温下搅拌均匀，加入I-MOM-2-Larotrectinib(63.84mg，0.11mmol)，产生的混合物升温至60度，反应2小时，冷却至室温，滴加三氟乙酸酐(0.16mL，0.24g,1.14mmol)，加完，混合物室温反应2小时，TLC跟踪反应过程，原料消失后，过滤去除固体物，剩余物硅胶柱层析分离(展开剂：0-50％乙酸乙酯-正庚烷，v/v,洗脱)，收集目标产物 洗脱液，浓缩得到黄色固体I-MOM-TfAc-2-Larotrectinib(48.79mg,0.061mmol,55％yield)，
在2mL反应瓶中，加入含有辅助酸金刚烷(SPI-Adaman,0.1mmol,23mg)的10％碳酸钠水溶液(w/v.0.75mL,0.33M)，加入乙醇(1mL),随后迅速加入I-MOM-TfAc-2-Larotrectinib(0.061mmol,48.79mg)，反应混合物室温下，激烈搅拌反应3h,TLC跟踪反应至原料转化完全，反应混合物转入3mL水中稀释，二氯甲烷萃取三次，每次5毫升，合并有机萃取相，无水硫酸钠干燥，过滤，减压浓缩，剩余物经过硅胶柱层析(展开剂：0-50％乙酸乙酯-石油醚，v/v,洗脱)，收集目标产物洗脱液，浓缩得到标记前体I(III)-SPIAd-MOM-2-Larotrectinib白色固体(38.53mg,2步总收率43％)。
实施例76
类似实施例75的方法制备I(III)-SPIAd-MOM-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-MOM-5-Larotrectinib(38mg，2步总收率43％)。
实施例77
制备标记前体I(III)-SPIAd-MEM-2-Larotrectinib
Figure PCTCN2019106690-appb-000070
在2mL反应器中,乙腈0.4mL，搅拌下，添加Oxone(67.63mg，0.11mmol),NaBr(0.011mmol,1.13mg),室温下搅拌均匀，加入 I-MEM-2-Larotrectinib(68.69mg，0.11mmol)，产生的混合物升温至60℃，激烈搅拌反应2小时，冷却至室温，滴加三氟乙酸酐(0.16mL，0.24g,1.14mmol,1.511C g/mL)，加完，混合物室温反应2小时，TLC跟踪反应过程，原料消失后，过滤去除固体物，浓缩有机相后，剩余物硅胶柱层析分离(展开剂：0-50％乙酸乙酯-正庚烷，v/v,洗脱)，收集目标产物洗脱液，浓缩得到无色固体I-MEM-TfAc-2-Larotrectinib(52.39mg,0.062mmol,56％yield)
在2mL反应瓶中，加入含有辅助酸金刚烷(SPI-Adaman,0.1mmol,23mg)的10％碳酸钠水溶液(w/v.0.75mL,0.33M)，加入乙醇(1mL),随后迅速加入I-MEM-TfAc-2-Larotrectinib(0.062mmol,52.39mg)，反应混合物室温下，激烈搅拌反应4h,TLC跟踪反应至原料转化完全，反应混合物转入3mL水中稀释，二氯甲烷萃取三次，每次5毫升，合并有机萃取相，无水硫酸钠干燥，过滤，减压浓缩，剩余物经过硅胶柱层析(展开剂：0-50％乙酸乙酯-石油醚，v/v,洗脱)，收集目标产物洗脱液，浓缩得到标记前体I(III)-SPIAd-MEM-2-Larotrectinib白色固体(30.23mg,2步总收率32％)。
实施例78
类似实施例77的方法制备I(III)-SPIAd-MEM-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-MEM-5-Larotrectinib(30mg，2步总收率32％)。
实施例79
制备标记前体I(III)-SPIAd-SEM-2-Larotrectinib
Figure PCTCN2019106690-appb-000071
在2mL反应器中,加入乙腈0.13mL、三氟乙酸(0.39mL，5.26mmol,0.6g,1.5351克/厘米 3)、Oxone(100mg,0.165mmol)，混合物冰水浴冷却至0-5度搅拌反应0.5小时，缓慢将I-SEM-2-Larotrectinib(73.32mg，0.11mmol)添加到激烈搅拌的混合物中，混合物在0-5度下继续搅拌反应1小时，加入乙醇(0.5mL)稀释，在迅速加入含有辅助酸金刚烷(SPI-Adaman(25.3mg,0.11mmol)的10％碳酸钠溶液(0.1mL)，并用10％碳酸钠溶液调节混合溶液pH9左右(注意：此步骤有气泡产生)。混合物0-5度下搅拌3小时，然后转入5mL水中稀释，DCM萃取三次，每次5mL，合并有机相，硫酸镁干燥，减压浓缩，剩余物经过硅胶柱层析(正庚烷/乙酸乙酯＝10/1)，得到标记前体I(III)-SPIAd-SEM-2-Larotrectinib白色固体(20.81mg,2步总收率21％)。
实施例80
类似实施例79的方法制备I(III)-SPIAd-SEM-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-SEM-5-Larotrectinib(20mg，2步总收率21％)。
实施例81
制备标记前体I(III)-SPIAd-THP-2-Larotrectinib
Figure PCTCN2019106690-appb-000072
在1mL反应器中,搅拌下，添加二氯甲烷0.13mL，过氧化叔丁醇(tBuOOH，TBHP，2.79g,31mmol),加入I-THP-2-Larotrectinib(68.25mg，0.11mmol)，产生的混合物冰水浴下冷却至零度，激烈搅拌1小时，TLC跟踪直到原料转化完 毕，待用。
在2mL反应器中，加入KOH(47.12mg,0.84mmol),二氯甲烷(0.47ml),SPIAd(39.1mg,0.17mmol),非均相混合物冰水浴下冷却至零度，激烈搅拌5分钟，混合物呈现乳白色悬浮液。将上述待用物料一次性转入到激烈搅拌的混合物中，并在零度下连续搅拌反应2小时，反应混合物逐渐变成黄色，TLC跟踪直到原料转化完毕，滤去不溶物，反应瓶用二氯甲烷洗涤三次，每次0.12mL，洗涤液体淋洗不溶物，收集二氯甲烷黄色液体。减压浓缩(20度下)蒸干二氯甲烷，再高真空度下抽干1小时，得到标记前体物I(III)-SPIAd-THP-2-Larotrectinib黄色固体(27.08mg,收率28.8％)。
实施例82
类似实施例81的方法制备I(III)-SPIAd-THP-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-THP-5-Larotrectinib(27mg,28％)。
实施例83
制备标记前体I(III)-SPIAd-EE-2-Larotrectinib
Figure PCTCN2019106690-appb-000073
在2mL反应器中,加入氯仿0.13mL、三氟乙酸0.3mL、三氟乙酸酐(0.9mL)、Oxone(H 3K 5O 18S 4＝614.76，101.44mg，0.165mmol)、I-EE-2-Larotrectinib(71.2mg，0.11mmol)，冰水浴冷却至零度，激烈搅拌下搅拌均匀，无水醋酸钾(0.53g,6.45mmol)缓慢添加到混合物中，加完，混合物0-5℃ 继续搅拌反应0.5小时，用水稀释，二氯甲烷萃取，合并萃取有机相，无水硫酸钠干燥，过滤，浓缩，剩余物用正庚烷乙酸乙酯洗涤，过滤的得到无色固体I-EE-TfAc-2-Larotrectinib(52.24mg,0.064mmol,58％yield).
在2mL反应瓶中，加入含有辅助酸金刚烷(SPI-Adaman(0.1mmol,23mg)的10％碳酸钠水溶液(w/v.0.75mL,0.33M)，加入乙醇(1mL),随后迅速加入I-EE-TfAc-2-Larotrectinib(0.096mmol,84.53mg)，反应混合物室温下，激烈搅拌反应4h,TLC跟踪反应至原料转化完全，反应混合物转入3mL中稀释，二氯甲烷萃取三次，每次5毫升，合并有机萃取相，无水硫酸钠干燥，过滤，减压浓缩，剩余物经过硅胶柱层析，用正庚烷/乙酸乙酯＝10/1洗脱，得到标记前体I(III)-SPIAd-EE-2-Larotrectinib白色固体(40.60mg,2步总收率43.8％)。
实施例84
类似实施例83的方法制备I(III)-SPIAd-EE-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-EE-5-Larotrectinib(40mg，2步总收率43％)。
实施例85
制备标记前体I(III)-SPIAd-Als-2-Larotrectinib
Figure PCTCN2019106690-appb-000074
在2mL反应器中,加入丙酮0.8mL,搅拌下，添加I-Als-2-Larotrectinib(91.91mg，0.14mmol)、mCPBA(62.86mg,0.22mmol)，混合物于10-15度下激烈搅拌反应1-2h，向反应混合物中添加SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠 溶液1.68mL,并用10％碳酸钠溶液调节pH8。混合物于10-15度下激烈搅拌2h，TLC跟踪直到原料转化完毕，反应液转入装有5mL的反应瓶中稀释，二氯甲烷萃取三次，每次5mL，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，过滤减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)，得到标记前体I(III)-SPIAd-Als-2-Larotrectinib黄色色固体(25.72mg,得率21％)。
实施例86
类似实施例85的方法制备I(III)-SPIAd-Als-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-Als-5-Larotrectinib(26mg,21％)。
实施例87
制备标记前体I(III)-SPIAd-PMP-2-Larotrectinib或
Figure PCTCN2019106690-appb-000075
在2mL反应器中,添加三氟乙酸0.53mL、氯仿0.18mL,搅拌下，添加I-PMP-2-Larotrectinib(96.37mg，0.15mmol)，氯化钠(0.59mg,0.01mmol),Oxone(H 3K 5O 18S 4＝614.76，138.32mg,0.225mmol)，混合物升温至80度，搅拌反应3小时，TLC跟踪至原料反应完全，然后减压浓缩去溶剂，剩余物中添加乙醇1.2mL,SPIAd(34.5mg,0.15mmol)溶解于10％碳酸钠溶液0.68mL,并用10％碳酸钠溶液调节pH9。混合物室温搅拌70分钟，TLC跟踪反应完成，将反应物转入3mL水中稀释，DCM萃取三次，每次5mL，合并有机相，无水硫酸镁干燥，减压浓缩，剩余物硅胶柱层析(0-40％乙酸乙酯-石油醚溶液洗脱)，得到标记前体I(III)-SPIAd-PMP-2-Larotrectinib黄色固体(43.39mg,得率33％)。
实施例88
类似实施例87的方法制备I(III)-SPIAd-PMP-5-Larotrectinib，得到产物白色固体I(III)-SPIAd-PMP-5-Larotrectinib(43mg,33％)。
步骤三：放射性同位素的制备
使用季铵盐(TEABC)代替毒性较大的K 222，使用乙腈冲洗阴离子交换盒洗脱富集的[ 18F]氟化物，脱水干燥时间﹤5min，提供了一条时间短、毒性低、放射化学纯度高的制备方法。[ 18F]-Larotrectinib标记物的制备流程如下：
步骤1、制备[ 18F]氟化物靶水：[ 18F]氟化物靶水通过1 8O(p,n) 18F核反应生产。使用GE PETTrace回旋加速器(40μA光束为2分钟可产生大约150mCi[ 18F]氟化物靶水)。通过氮气压力将[ 18F]氟化物靶水递送到 18O-富集水的无菌铅保护热室，用这种方法生产的[ 18F]氟化物靶水在用于研究之前,通常用Milli-Q(密理博公司超纯水仪器)超纯化水进一步稀释成1-3mCi/毫升[ 18F]氟化物靶水液体。
步骤2、QMA阴离子交换固相萃取盒(QMA)富集[ 18F]氟化物：将含有适量的[ 18F]氟化物的目标水的等分试样,在氮气流冲洗下，缓慢通过阴离子交换固相萃取盒(QMA)，该阴离子交换固相萃取盒(QMA)事先通过使用NaHCO 3(aq)(8.4％，1mL)和水(20mL，直到pH指示剂为中性)的冲洗而预活化过，将[ 18F]氟化物富集在QMA阴离子交换固相萃取盒(QMA)上，将 18O和其它不纯物分离洗脱除去，得到[ 18F]氟化物QMA阴离子交换固相萃取盒(QMA)的[ 18F]氟源。
步骤3、洗脱QMA阴离子交换固相萃取盒(QMA)上富集的[ 18F]氟化物，得到[ 18F]氟化物季铵盐或无机盐溶液：使用有机或无机碱(例如，一定数量的四乙基碳酸氢铵，例如8mg)溶解在乙腈和水(1mL，v/v 7:3)或乙腈(1mL)或甲醇(1mL)或乙醇(1mL)中所得的溶液，冲洗富集在QMA阴离子交换固相萃取盒(QMA)上的[ 18F]氟化物，将[ 18F]氟化物洗脱到用特氟隆衬垫隔膜密封的V形小瓶中，得到[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇溶液。
步骤4、制备干燥的[ 18F]氟化物季铵盐或无机盐：将装有[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇或乙醇溶液的特氟隆衬垫隔膜密封的V形小瓶加热至95-110℃，同时使氮气通过P 2O 5-Drierite TM柱干燥后吹扫V形小瓶， 随后通过通气的小瓶排出尾气。当在小瓶中没有液体可见时，将其从热浴中取出，添加无水乙腈(1mL)，并恢复加热直至干燥。将该步骤重复另外三次。然后将小瓶在氮气流下，在室温下冷却，得到干燥的[ 18F]氟化物有机盐或无机盐，如[ 18F]KF/K 2CO 3/K 2.2.2、[ 18F]KF/K 2C 2O 4/K 2.2.2、[ 18F]KF/KOTf、[ 18F]Et 4NF、[ 18F]Et 4NHCO 3、[ 18F]Et 4NOMs、[ 18F]Et 4NOTf，其放射性[ 18F]氟化物回收率，根据采用的洗脱工艺不同而有差异。
步骤5、[ 18F]-Larotrectinib标记物反应体系的构建：取装有干燥的[ 18F]氟化物有机盐或无机盐(活度计测量(t 0)活度)的V形小瓶，添加所需溶剂(例如DMF)重新溶解，再添加标记前体，在一定条件下反应，得到[ 18F]-Larotrectinib未脱保护的标记物的粗品反应液。
步骤6、[ 18F]-Larotrectinib未脱保护的标记物脱保护：采用不添加或添加一定量的有机碱或无机碱或有机酸或无机酸至反应液中，在加热条件下脱除羟基保护基，得到[ 18F]-Larotrectinib标记物的粗品反应液。
步骤7、[ 18F]-Larotrectinib标记物的分离纯化：采用半制备HPLC或Waters Sep-Pak C-18小柱纯化制备高纯度的[ 18F]-Larotrectinib标记产物，并用溶剂淋洗进无菌真空瓶，60度下氮气吹干20分钟，用盐水重新复配，其中含有100ul，25％的维生素C的水溶液，100ul，20％吐温80的乙醇溶液，即得[18F]-Larotrectinib标记物注射液。
步骤8、[ 18F]-Larotrectinib标记物的分析鉴定：通过放射性HPLC(60:40 CH 3CN:H 2O+0.1N甲酸铵，Phenomenex Luna C 18,250×4.6mm,5μm,UV at 254nm；CH 3CN/0.1M NH4·HCO 2(aq)(v/v,7/3)，流速1.0mL/min)和放射性TLC(EtOAc+0～5％EtOH)测定产物标识和纯度(放射化学纯度和化学纯度)。产物的放射化学纯度>90-99％。产物的化学纯度>90-99％。将放射化学产率确定为从在将标记前体加入DMF稀释的[ 18F]Et 4NHCO 3溶液的V型小瓶中的活度量作为最终产物分离的放射性的百分比，并且没有衰变校正。放射化学得率20～45.3(未经衰减校正)，放射化学纯度大于99％，比活度2.56～18Ci/μmol)。
下面通过实施例具体说明：
实施例89、[ 18F]氟化物有机盐或无机盐制备工艺
将含有适量的[ 18F]氟化物的目标水的等分试样，在氮气流冲洗下，缓慢通 过阴离子交换固相萃取盒(QMA)，该阴离子交换固相萃取盒(QMA)事先通过使用NaHCO 3(aq)(8.4％，1mL)和水(20mL，直到pH值为中性)的冲洗而预活化过，将[ 18F]氟化物富集在QMA阴离子交换固相萃取盒(QMA)上，将 18O和其它不纯物分离洗脱除去，得到[ 18F]氟化物QMA阴离子交换固相萃取盒(QMA)的[ 18F]氟源。
使用不同的有机或无机碱溶解在乙腈和水(1mL，v/v 7:3)或乙腈(1mL)或甲醇(1mL)或乙醇(1mL)中所得的溶液，冲洗富集在QMA阴离子交换固相萃取盒(QMA)上的[ 18F]氟化物，将[ 18F]氟化物洗脱到用特氟隆衬垫隔膜密封的V形小瓶中，得到[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇溶液。
将装有[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇或乙醇溶液的特氟隆衬垫隔膜密封的V形小瓶加热至95-110℃，同时使氮气通过P 2O 5-Drierite TM柱干燥后吹扫V形小瓶，随后通过通气的小瓶排出尾气。当在小瓶中没有液体可见时，将其从热浴中取出，添加无水乙腈(1mL)，并恢复加热直至干燥。将该步骤重复另外三次。然后将小瓶在氮气流下，在室温下冷却，得到干燥的[ 18F]氟化物有机盐或无机盐，如[ 18F]KF/K 2CO 3/K 2.2.2、[ 18F]KF/K 2C 2O 4/K 2.2.2、[ 18F]KF/KOTf、[ 18F]Et 4NF、[ 18F]Et 4NHCO 3、[ 18F]Et 4NOMs、[ 18F]Et 4NOTf，其放射性[ 18F]氟化物回收率，根据采用的洗脱工艺不同而有差异。试验数据如(表一、不同洗脱剂和有机或无机碱对[ 18F]氟化物洗脱效率的影响)和(表二、不同有机或无机碱的负载量对[ 18F]氟化物洗脱效率的影响，以乙腈作为洗脱溶剂)。
表一、不同洗脱剂和有机碱(8mg)或无机碱(8mg)对[ 18F]氟化物洗脱效率的影响
Figure PCTCN2019106690-appb-000076
Figure PCTCN2019106690-appb-000077
表二、不同有机或无机碱用量对[ 18F]氟化物洗脱效率的影响，以1mL乙腈作为洗脱溶剂
Figure PCTCN2019106690-appb-000078
实施例90
由标记前体I(III)-SPIAd-Bz-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000079
方案一、按照[ 18F]-Larotrectinib标记物的制备流程，取[ 18F]氟源(0.5mL，活度计测量(t 0)活度1.5mCi)QAM[ 18F]氟化物，用N,N,N,N-四乙基甲烷磺酸铵(TBAOMs，8.0mg)溶解于1mL乙腈的溶液洗脱氟源QAM[ 18F]氟化物阴离子交换固相萃取盒(QMA)至V型小瓶中，所得[ 18F]Et 4NOMs的乙腈溶液，经过无水乙腈反复共沸蒸发脱水至干，剩余物用无水DMF(0.4mL)稀释成20mg/mL的[ 18F]Et 4NOMs溶液。
从上述DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Bz-2-Larotrectinib白色固体(4.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至120度反应20分钟,TLC跟踪标记前体物I(III)-SPIAd-Bz-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Bz2--Larotrectinib标记产物。
向反应混合物中加入无水K 2CO 3(0.86mg),加热至100度反应10分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液(15μL，1.05g/cm 3)滴加到溶液中和至中性。将反应物进一步用HPLC缓冲液(60:40 CH 3CN:H 2O+0.1N甲酸铵，2mL)稀释,并通过已经依次用乙醇(1mL)和水(5mL)冲洗而活化的Waters C-18Sep-Pak。用水(2mL)冲洗Sep-Pak，用乙醇(1mL)洗脱所需产物,淋洗进无菌真空瓶，60度下氮气吹干20分钟，用盐水重新复配，其中含有100ul，25％的维生素C的水溶液，100ul，20％吐温80的乙醇溶液，即得[ 18F]-Larotrectinib标记物注射液。
样品经过放射TLC分析(硅胶板，100％乙酸乙酯展层)确定放射化学转化(RCC)，通过放射性HPLC(60:40 CH 3CN:H 2O+0.1N甲酸铵，Phenomenex Luna C-18柱)和放射性TLC(硅胶板，100％乙酸乙酯展层)测定产物标识和纯度。产物的放射化学纯度>93％，化学纯度>95％。并用放射性与非放射活性对照品共注射法，经过放射性检测器和非放射性紫外检测器双重检测器确定出峰位置的一致性标识标记产物。将放射化学产率确定为在将碘鎓前体加入到DMF稀释的[ 18F]Et 4NOMs溶液，从V型小瓶中的活度量中作为最终产物分离的放射性的百分比，并且没有衰变校正。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为28.56％，并且在最终制剂中获得比活度(18.21Ci/μmol)。保护基脱除率95％。
方案二、操作过程同方案一，不同处在于,采用DMF溶液中分出400uL样品分别含有[ 18F]KF/K 2CO 3/K 2.2.2、[ 18F]KF/K 2C 2O 4/K 2.2.2、[ 18F]KF/KOTf、[ 18F]Et 4NF、[ 18F]Et 4NHCO 3、[ 18F]Et 4NOMs、[ 18F]Et 4NOTf(均为1.35mCi),分别加入到添加有标记前体物I(III)-SPIAd-Bz-2-Larotrectinib白色固体(4.0mg)的V型反应瓶中。混合物密闭下加热至120度反应20分钟,TLC跟踪标记前体物I(III)-SPIAd-Bz-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Bz-2-Larotrectinib标记产物。后续步骤分别同方案一，得到产物的放射化学纯度和化学纯度>99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)及比活度见下表三。
表三、不同有机或无机碱用量对[ 18F]-2-Larotrectinib放射化学产率及比活度的影响
Figure PCTCN2019106690-appb-000080
方案三、操作过程同方案一，不同处在于采用N,N,N,N-四乙基甲烷磺酸铵(TBAOMs，8mg)溶解于1mL乙腈的溶液洗脱氟源QAM[ 18F]氟化物阴离子交换固相萃取盒(QMA)至V型小瓶中，所得[ 18F]Et 4NOMs的乙腈溶液，经过无水乙腈反复共沸蒸发脱水至干，剩余物用不同无水溶剂DMF(0.4mL)、DMSO(0.4mL)、DMA(0.4mL)、CH3CN(0.4mL)、NMP(0.4mL)稀释成10mg/mL的[ 18F]Et 4NOMs溶液。后续步骤分别同方案一，得到产物的放射化学纯度和化学纯度>99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)及比活度见下表四。
表四、不同溶剂种类对[ 18F]-2-Larotrectinib放射化学产率及比活度的影响
Figure PCTCN2019106690-appb-000081
方案四、操作过程同方案一，不同处在于,分别采用不同数量的N,N,N,N-四乙基甲烷磺酸铵(TBAOMs，1mg、4.0mg、8mg、10mg、12mg)溶解于1mL乙腈的溶液洗脱氟源QAM[ 18F]氟化物阴离子交换固相萃取盒(QMA)至V型小瓶中，所得[ 18F]Et 4NOMs的乙腈溶液，经过无水乙腈反复共沸蒸发脱水至干，剩余物用无水DMF(0.4mL)稀释成10mg/mL的[ 18F]Et 4NOMs溶液。后续步骤分别同方案一，得到产物的放射化学纯度和化学纯度>99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)及比活度见下表五。
表五、不同有机或无机碱用量对[ 18F]-2-Larotrectinib放射化学产率及比活度的影响
Figure PCTCN2019106690-appb-000082
方案五、操作过程同方案一，不同处在于,将DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Bz-2-Larotrectinib白色固体(4.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至不同温度100℃、110℃、120℃、135℃、145℃、155℃、160℃分别反应20分钟,TLC跟踪标记前体物I(III)-SPIAd-Bz-2-Larotrectinib基本消失。后续步骤分别同方案一，得到产物的放射化学纯度和化学纯度>99％。[ 18F]-2-Larotrectinib 的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)及比活度见下表六。
表六、不同反应温度对[ 18F]-2-Larotrectinib放射化学产率及比活度的影响
Figure PCTCN2019106690-appb-000083
方案六、操作过程同方案一，不同处在于,将DMF溶液中分出400uL样品,加入到添加有不同数量的标记前体物I(III)-SPIAd-Bz-2-Larotrectinib白色固体(0.5mg、1.0mg、2.0mg、4.0mg、6mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至145℃反应20分钟,TLC跟踪标记前体物I(III)-SPIAd-Bz-2-Larotrectinib基本消失。后续步骤分别同方案一，得到产物的放射化学纯度和化学纯度>99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)及比活度见下表七。
表七、不同标记前体用量对[ 18F]-2-Larotrectinib放射化学产率及比活度的影响
Figure PCTCN2019106690-appb-000084
方案七、操作过程同方案一，不同处在于,将DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Bz-2-Larotrectinib白色固体(0.5mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下分别加热至120°C、135℃、145℃、155℃、160℃反应不同时间5min、10min、15min、20min,TLC跟踪标记前体物I(III)-SPIAd-Bz-2-Larotrectinib基本消失。后续步骤分别同方案一，得到产物的放射化学纯度和化学纯度>99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi) 及比活度见下表八。
表八、不同标记反应时间对[ 18F]-2-Larotrectinib放射化学产率及比活度的影响
Figure PCTCN2019106690-appb-000085
方案八、按照[ 18F]-Larotrectinib标记物的制备流程，取[ 18F]氟源(0.5mL，活度计测量(t 0)活度1.5mCi)QAM[ 18F]氟化物，用N,N,N,N-四乙基甲烷磺酸铵(TBAOMs，8.0mg)溶解于1mL乙腈的溶液洗脱氟源QAM[ 18F]氟化物阴离子交换固相萃取盒(QMA)至V型小瓶中，所得[ 18F]Et 4NOMs的乙腈溶液，经过无水乙腈反复共沸蒸发脱水至干，剩余物用无水DMF(0.4mL)稀释成20mg/mL的[ 18F]Et 4NOMs溶液。
从上述DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Bz-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Bz-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Bz-2-Larotrectinib标记产物。
向反应混合物中加入无水叔丁醇钾(KOtBu，0.70mg),加热至80度反应8分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液(15μL，1.05g/cm 3)滴加到溶液中和至中性。将反应物进一步用HPLC缓冲液(60:40CH 3CN:H 2O+0.1N甲酸铵，2mL)稀释,并通过已经依次用乙醇(1mL)和水(5mL)冲洗而活化的Waters C-18Sep-Pak。用水(2mL)冲洗Sep-Pak，用乙醇(1mL)洗脱所需产物,淋洗进无菌真空瓶，60度下氮气吹干20分钟，用盐水重新复配，其中含有100ul，25％的维生素C的水溶液，100ul，20％吐温80的乙醇溶液，即得[ 18F]-2-Larotrectinib标记物注射液。
样品经过放射TLC分析(硅胶板，100％乙酸乙酯展层)确定放射化学转化(RCC)，通过放射性HPLC(60:40 CH 3CN:H 2O+0.1N甲酸铵，Phenomenex Luna C-18柱)和放射性TLC(硅胶板，100％乙酸乙酯展层)测定产物标识和纯度。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。并用放射性与非放射活性对照品共注射法，经过放射性检测器和非放射性紫外检测器双重检测器确定出峰位置的一致性标识标记产物。将放射化学产率确定为在将碘鎓前体加入到DMF稀释的[ 18F]Et 4NOMs溶液，从V型小瓶中的活度量中作为最终产物分离的放射性的百分比，并且没有衰变校正。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为41.82％，并且在最终制剂中获得比活度(27.11Ci/μmol)。
实施例91
类似实施例90的方法，由标记前体I(III)-SPIAd-Bz-5-Larotrectinib制备[18F]-5-Larotrectinib标记物，产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为41.15％，并且在最终制剂中获得比活度(27.13Ci/μmol)。
实施例92
由标记前体I(III)-SPIAd-TBS-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000086
按照[ 18F]-Larotrectinib标记物的制备流程，取[ 18F]氟源(0.5mL，活度计测量(t 0)活度1.5mCi)QAM[ 18F]氟化物，用N,N,N,N-四乙基甲烷磺酸铵(TBAOMs，8.0mg)溶解于1mL乙腈的溶液洗脱氟源QAM[ 18F]氟化物阴离子交换固相萃取盒(QMA)至V型小瓶中，所得[ 18F]Et 4NOMs的乙腈溶液，经过无水乙腈反复共沸蒸发脱水至干，剩余物用无水DMF(0.4mL)稀释成20mg/mL的[ 18F]Et 4NOMs溶液。
从上述DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-TBS-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中 ([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-TBS-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-2-Larotrectinib标记产物。
将反应物进一步用HPLC缓冲液(60:40 CH 3CN:H 2O+0.1N甲酸铵，2mL)稀释,并通过已经依次用乙醇(1mL)和水(5mL)冲洗而活化的Waters C-18 Sep-Pak。用水(2mL)冲洗Sep-Pak，用乙醇(1mL)洗脱所需产物,淋洗进无菌真空瓶，60度下氮气吹干20分钟，用盐水重新复配，其中含有100ul，25％的维生素C的水溶液，100ul，20％吐温80的乙醇溶液，即得[ 18F]-2-Larotrectinib标记物注射液。
样品经过放射TLC分析(硅胶板，100％乙酸乙酯展层)确定放射化学转化(RCC)，通过放射性HPLC(60:40 CH 3CN:H 2O+0.1N甲酸铵，Phenomenex Luna C-18柱)和放射性TLC(硅胶板，100％乙酸乙酯展层)测定产物标识和纯度。产物的放射化学纯度和化学纯度>99％。并用放射性与非放射活性对照品共注射法，经过放射性检测器和非放射性紫外检测器双重检测器确定出峰位置的一致性标识标记产物。将放射化学产率确定为在将碘鎓前体加入到DMF稀释的[ 18F]Et 4NOMs溶液，从V型小瓶中的活度量中作为最终产物分离的放射性的百分比，并且没有衰变校正。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.82％，并且在最终制剂中获得比活度(29.82Ci/μmol)。
实施例93
类似实施例92的方法，由标记前体I(III)-SPIAd-TBS-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.21％，并且在最终制剂中获得比活度(29.81Ci/μmol)。
实施例94
由标记前体I(III)-SPIAd-SEM-2-Larotrectinib制备[ 18F]2--Larotrectinib标记物
Figure PCTCN2019106690-appb-000087
此操作同实施例91。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.82％，并且在最终制剂中获得比活度(29.82Ci/μmol)。
实施例95
类似实施例94的方法，由标记前体I(III)-SPIAd-SEM-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.55％，并且在最终制剂中获得比活度(29.80Ci/μmol)。
再取样经过放射性TLC检测至脱保护完成。反应混合物用5N氢氧化钠(5N，0.2mL)中和,用HPLC流动相(10％乙醇，28mM盐酸，20nM醋酸铵，pH2,0.5mL)稀释。稀释液注入半制备HPLC(静相：哈密顿PRP-1，250x10mm,10um；流动相同上，3.5mL/min,t R＝-17min)，分步收集含有产品的洗脱液，用活度计检测活度，并计算分离获得率80％(未计衰减校正)，总时长(从t 0至合成结束EOS)75±2min。放化纯度95-99％。脱保护转化率98％以上。
混合物(2uL)经过TLC薄板层析(展层剂：100％乙酸乙酯)确定标记率(RCC), 然后用15mL水稀释，过C18填料的固相萃取小柱，水(24mL)洗脱，乙腈(1.5mL)冲洗收集于微型瓶中。
取混合物(20uL)和氟-19标准对照品( 19F-Larocetrinib)共注射到放射HPLC中，确定氟-18标记产物( 18F-Larocetrinib)。剩余反应混合物，反应混合物用5N氢氧化钠(5N，0.2mL)中和,用HPLC流动相(10％乙醇，28mM盐酸，20nM醋酸铵，pH2,0.5mL)稀释。稀释液注入半制备HPLC(静相：哈密顿PRP-1，250x 10mm,10um；流动相同上，3.5mL/min,t R＝-17min)，分步收集含有产品的洗脱液，用活度计检测活度，并计算分离获得率80％(未计衰减校正)，总时长(从t 0至合成结束EOS)75±2min。放化纯度95-99％。脱保护转化率98％以上。
实施例96
由标记前体I(III)-SPIAd-TBDPS-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000088
此操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.80％，并且在最终制剂中获得比活度(29.84Ci/μmol)。
实施例97
类似实施例96的方法，由标记前体I(III)-SPIAd-TBDPS-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.50％，并且在最终制剂中获得比活度(29.83Ci/μmol)。
实施例98
由标记前体I(III)-SPIAd-TIPS-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000089
此操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.89％，并且在最终制剂中获得比活度(29.82Ci/μmol)。
实施例99
类似实施例98的方法，由标记前体I(III)-SPIAd-TIPS-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.23％，并且在最终制剂中获得比活度(29.31Ci/μmol)。
实施例100
由标记前体I(III)-SPIAd-Teoc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000090
此操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.82％，并且在最终制剂中获得比活度(29.80Ci/μmol)。
实施例101
类似实施例100的方法，由标记前体I(III)-SPIAd-TPIS-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.27％，并且在最终制剂中获得比活度(29.31Ci/μmol)。
实施例102
由标记前体I(III)-SPIAd-Piv-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000091
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Piv-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Piv-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Piv-2-Larotrectinib标记产物。
向反应混合物中加入甲醇钠粉末(NaOMe,0.71mg),加热至90度，8分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.83％，并且在最终制剂中获得比活度(29.85Ci/μmol)。
实施例103
类似实施例102的方法，由标记前体I(III)-SPIAd-Piv-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.64％，并且在最终制剂中获得比活度(29.44Ci/μmol)。
实施例104
由标记前体I(III)-SPIAd-Ac-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000092
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Ac-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Ac-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Ac-2-Larotrectinib标记产物。
向反应混合物中加入甲醇钠粉末(NaOMe,0.11mg),加热至80度，8分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.84％，并且在最终制剂中获得比活度(29.88Ci/μmol)。
实施例105
类似实施例104的方法，由标记前体I(III)-SPIAd-Ac-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.54％，并且在最终制剂中获得比活度(29.25Ci/μmol)。
实施例106
由标记前体I(III)-SPIAd-Tf-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000093
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Tf-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Tf-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Tf-2-Larotrectinib标记产物。
向反应混合物中加入乙醇钠粉末(NaOEt,0.15mg),加热至80度，6分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.45％，并且在最终制剂中获得比活度(29.65Ci/μmol)。
实施例107
类似实施例106的方法，由标记前体I(III)-SPIAd-Tf-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶 中([ 18F]Et 4NOMs通常为1.35mCi)为45.78％，并且在最终制剂中获得比活度(29.54Ci/μmol)。
实施例108
由标记前体I(III)-SPIAd-CAc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000094
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-CAc-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-CAc-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-CAc-2-Larotrectinib标记产物。
向反应混合物中加入乙醇钠粉末(NaOEt,0.15mg),加热至80度，6分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.83％，并且在最终制剂中获得比活度(29.87Ci/μmol)。
实施例109
类似实施例108的方法，由标记前体I(III)-SPIAd-CAc-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.25％，并且在最终制剂中获得比活度(29.12Ci/μmol)。
实施例110
由标记前体I(III)-SPIAd-DCAc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000095
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-DCAc-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-DCAc-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-DCAc-2-Larotrectinib标记产物。
向反应混合物中加入甲醇钠粉末(NaOMe,0.11mg),加热至80度，5分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度和化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应 瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.85％，并且在最终制剂中获得比活度(29.86Ci/μmol)。
实施例111
类似实施例110的方法，由标记前体I(III)-SPIAd-DCAc-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.53％，并且在最终制剂中获得比活度(29.24Ci/μmol)。
实施例112
由标记前体I(III)-SPIAd-Moc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000096
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Moc-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Moc-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Moc-2-Larotrectinib标记产物。
向反应混合物中加入氢氧化钾(KOH,0.37mg),加热至100度，12分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率89.8％以上。产物的放射化学纯度大于96.3％,化学纯度大于91.3％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为35.45％，并且在最终制剂中获得比活度(22.33Ci/μmol)。
实施例113
类似实施例112的方法，由标记前体I(III)-SPIAd-Moc-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率89％，产物的放射化学纯度>96％,化学纯度>91％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为35.56％，并且在最终制剂中获得比活度(22.23Ci/μmol)。
实施例114
由标记前体I(III)-SPIAd-Eoc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000097
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Eoc-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC 跟踪标记前体物I(III)-SPIAd-Eoc-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Eoc-2-Larotrectinib标记产物。
向反应混合物中加入氢氧化钾(KOH,0.37mg),加热至100度，12分钟，将反应在0℃冰浴中冷却，然后加入10％HCl水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率90.2％以上。产物的放射化学纯度大于97.5％,化学纯度大于90.1％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为32.15％，并且在最终制剂中获得比活度(21.43Ci/μmol)。
实施例115
类似实施例114的方法，由标记前体I(III)-SPIAd-Eoc-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率90％，产物的放射化学纯度>97％,化学纯度>90％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为32.35％，并且在最终制剂中获得比活度(21.14Ci/μmol)。
实施例116
由标记前体I(III)-SPIAd-Boc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000098
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记 前体物I(III)-SPIAd-Boc-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Boc-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Boc-2-Larotrectinib标记产物。
向反应混合物中加入三氟乙酸(CF 3COOH,0.75mg),加热至100度，6分钟，将反应在0℃冰浴中冷却，然后加入10％NaOH水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率100％以上。产物的放射化学纯度大于99％,化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为42.35％，并且在最终制剂中获得比活度(28.25Ci/μmol)。
实施例117
类似实施例116的方法，由标记前体I(III)-SPIAd-Boc-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度和化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.35％，并且在最终制剂中获得比活度(29.51Ci/μmol)。
实施例118
由标记前体I(III)-SPIAd-Troc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000099
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Troc-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Troc-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Troc-2-Larotrectinib标记产物。
向反应混合物中加入乙酸(CH 3COOH,0.35mg),锌粉(Zn，0.82mg),加热至100度，8分钟，将反应在0℃冰浴中冷却，然后加入10％NaOH水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率95.8％以上。产物的放射化学纯度大于97.6％,化学纯度大于95％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为38.63％，并且在最终制剂中获得比活度(25.43Ci/μmol)。
实施例119
类似实施例118的方法，由标记前体I(III)-SPIAd-Troc-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率95％，产物的放射化学纯度>97.5％,化学纯度>97.5％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为38.35％，并且在最终制剂中获得比活度(25.41Ci/μmol)。
实施例120
由标记前体I(III)-SPIAd-PMB-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000100
Figure PCTCN2019106690-appb-000101
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-PMB-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-PMB-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-PMB-2-Larotrectinib标记产物。
向反应混合物中加入2,3-二氯-5,6-二氰对苯醌(DQQ,0.0033mmol,0.75mg),加热至100度，12分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率91.7％以上。产物的放射化学纯度大于95.6％,化学纯度大于90.7％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为37.43％，并且在最终制剂中获得比活度(23.12Ci/μmol)。
实施例121
类似实施例120的方法，由标记前体I(III)-SPIAd-PMB-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率95％，产物的放射化学纯度>97.5％,化学纯度>97.5％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为38.35％，并且在最终制剂中获得比活度(25.40Ci/μmol)。
实施例122
由标记前体I(III)-SPIAd-PMP-Larotrectinib制备[ 18F]-Larotrectinib标记物
Figure PCTCN2019106690-appb-000102
Figure PCTCN2019106690-appb-000103
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-PMP-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-PMP-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-PMP-2-Larotrectinib标记产物。
向反应混合物中加入硝酸铈铵(CAN，0.0033mmol,1.81mg),加热至100度，12分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率92.21％以上。产物的放射化学纯度大于95.8％,化学纯度大于91.1％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为37.87％，并且在最终制剂中获得比活度(23.52Ci/μmol)。
实施例123
类似实施例122的方法，由标记前体I(III)-SPIAd-PMP-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率93％，产物的放射化学纯度>95.5％,化学纯度>91.5％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为37.65％，并且在最终制剂中获得比活度(23.81Ci/μmol)。
实施例124
由标记前体I(III)-SPIAd-MOM-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000104
Figure PCTCN2019106690-appb-000105
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-MOM-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-MOM-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-MOM-2-Larotrectinib标记产物。
向反应混合物中加入6N盐酸(0.0033mmol,0.65mg),加热至80度，12分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率92.4％以上。产物的放射化学纯度大于95.2％,化学纯度大于91.4％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为36.35％，并且在最终制剂中获得比活度(22.12Ci/μmol)。
实施例125
类似实施例124的方法，由标记前体I(III)-SPIAd-MOM-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率93％，产物的放射化学纯度>95.8％,化学纯度>91.8％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为36.25％，并且在最终制剂中获得比活度(22.27Ci/μmol)。
实施例126
由标记前体I(III)-SPIAd-MEM-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000106
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-MEM-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-MEM-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-MEM-2-Larotrectinib标记产物。
向反应混合物中加入溴化镁(0.0033mmol,0.6mg),加热至155度，10分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率96.7％以上。产物的放射化学纯度大于96.3％,化学纯度大于96.2％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为37.29％，并且在最终制剂中获得比活度(23.14Ci/μmol)。
实施例127
类似实施例126的方法，由标记前体I(III)-SPIAd-MEM-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率97％，产物的放射化学纯度>96％,化学纯度>96％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为37.25％，并且在最终制剂中获得比活度(23.21Ci/μmol)。
实施例128
由标记前体I(III)-SPIAd-THP-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000107
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-THP-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-THP-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-THP-2-Larotrectinib标记产物。
向反应混合物中加入对甲苯磺酸(0.0033mmol,0.56mg),加热至155度，5分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率97.5％以上。产物的放射化学纯度大于98.2％,化学纯度大于96.4％。[ 18F]-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为41.32％，并且在最终制剂中获得比活度(27.04Ci/μmol)。
实施例129
类似实施例128的方法，由标记前体I(III)-SPIAd-THP-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率97％，产物的放射化学纯度>99％,化学纯度>97％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为41.55％，并且在最终制剂中获得比 活度(27.81Ci/μmol)。
实施例130
由标记前体I(III)-SPIAd-EE-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000108
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-EE-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-EE-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-EE-2-Larotrectinib标记产物。
向反应混合物中加入对甲苯磺酸(0.0033mmol,0.56mg),加热至155度，5分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率99.8％以上。产物的放射化学纯度大于99％,化学纯度大于99％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.14％，并且在最终制剂中获得比活度(28.23Ci/μmol)。
实施例131
类似实施例130的方法，由标记前体I(III)-SPIAd-EE-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率100％，产物的放射化学纯度>99％,化学纯度>99％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反 应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为45.50％，并且在最终制剂中获得比活度(28.51Ci/μmol)。
实施例132
由标记前体I(III)-SPIAd-Als-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物
Figure PCTCN2019106690-appb-000109
按照[ 18F]-Larotrectinib标记物的制备流程，制得无水DMF的[ 18F]Et 4NOMs溶液(20mg/mL，0.4mL)。从DMF溶液中分出400uL样品,加入到添加有标记前体物I(III)-SPIAd-Als-2-Larotrectinib白色固体(1.0mg)的V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)。混合物密闭下加热至155度反应12分钟,TLC跟踪标记前体物I(III)-SPIAd-Als-2-Larotrectinib基本消失，放射性TLC跟踪反应混合物取样(1-2uL)经过检测有[ 18F]-Als-2-Larotrectinib标记产物。
向反应混合物中加入吗啉与35％甲酸溶液(1：1，1.84mg)，添加催化量四苯基磷钯,加热至80度，8分钟，将反应在0℃冰浴中冷却，然后加入10％NaHCO 3水溶液滴加到溶液中和至中性。后续操作同实施例92。脱保护转化率大于99％以上。产物的放射化学纯度大于96.5％,化学纯度大于96.7％。[ 18F]-2-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为41.54％，并且在最终制剂中获得比活度(26.72Ci/μmol)。
实施例133
类似实施例132的方法，由标记前体I(III)-SPIAd-Als-5-Larotrectinib制备[ 18F]-5-Larotrectinib标记物。产物脱保护率大于99％，产物的放射化学纯度>97％,化学纯度>97％。[ 18F]-5-Larotrectinib的未校正的放射化学产率相对于V型反应瓶中([ 18F]Et 4NOMs通常为1.35mCi)为41.75％，并且在最终制剂中获得比活度(26.71Ci/μmol)。

Claims (14)

  1. 一种[ 18F]-标记Larotrectinib化合物，其特征在于，包括具有以下结构式 18F-Larotrectinib化合物及其类似物：
    Figure PCTCN2019106690-appb-100001
  2. 一种权利要求1所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，该方法包括以下步骤：
    步骤一：羟基保护：碘代Larotrectinib类似物前体(I-Larotrectinib)的活性羟基官能团的保护；
    步骤二：标记前体制备：步骤一所得活性羟基被保护的碘代Larotrectinib类似物前体(I-Larotrectinib)中碘活化制备三氟醋酸碘代Larotrectinib类似物，随后与金刚烷取代的辅助酸反应制备标记前体：螺环高价碘(III)代羟基保护的Larotrectinib类似物；
    步骤三：氟-18标记产物的制备：标记前体与氟-18放射性源取代反应，制 备羟基保护的18F-Larotrectinib的合成及18F-Larotrectinib类似物的合成，随后脱保护得到18F-Larotrectinib及18F-Larotrectinib类似物。
  3. 根据权利要求2所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤一所述的碘代Larotrectinib类似物前体包括如下结构式：
    Figure PCTCN2019106690-appb-100002
    上式中，R1、R2分别独立代表苯基取代基，R1、R2各自独立地选自H、卤素、羟基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C6-10芳基、C4-10杂环烷基、C6-10杂芳基组成的组；R1、R2各自独立地与R3组成组；
    上式中，R3具体代表为H；
    所述的活性羟基官能团的保护是指通过酯化反应或醚化反应，将R3通过以下官能团取代，从而保护活性羟基，取代的官能团包括三甲基硅氧醚(TMS)、叔丁基二甲基硅氧烷醚(TBDMS)、三乙基硅氧醚(TES)、叔丁基二苯基硅氧烷醚(TBDPS)、甲醚(Me)、苄醚(Bn)、三苯甲基醚(Tr)、对甲氧基三苯甲基醚(MMT)、二甲氧基三苯甲基醚(DMT)、叔丁基醚(tBu)、甲氧基甲醚(MOM)、2-甲氧基乙氧基甲基醚(MEM)、甲硫基甲醚(MTM)、苄氧基甲基醚(BOM)、对甲氧基苄基醚(PMB)、对甲氧基苄氧基甲基醚(PMBOM)、3,4-二甲氧基苄基醚(DMB)、四氢吡喃醚(THP)、甲氧羰基(Moc)、乙氧羰基(Eoc)、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、9-芴甲氧基羰酰基(Fmoc)、乙酰基(Ac)、三氟乙酰基(TfAc)、氯乙酰基(CAc)、二氯乙酰基(DCAc)、苯甲酰基(Bz)、特戊酰基(Pv)、甲磺酰基(Ms)、苄基磺酸酰基(Bs)、烯丙基磺酸酰基(Bs)、烯丙基氧羰基(Als)、烯丙氧羰基、C1-16烷酰基、C2-16烯酰基、C3-6炔酰基、C4-10环烷基、C7-16芳酰基、C4-10杂环烷酰基；所述的烷酰基优选乙酰基；所述的芳酰基优先苯甲酰基；所述的取代烷酰基，特戊酰基或苯乙酰基。
  4. 根据权利要求2或3所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤一所述的碘代Larotrectinib类似物前体的结构式为；
    Figure PCTCN2019106690-appb-100003
  5. 根据权利要求4所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤一是对碘代Larotrectinib类似物前体中的活性羟基进行取代，实现保护，取代方法包括：
    (1)苯甲酰氯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100004
    ，或者，
    Figure PCTCN2019106690-appb-100005
    (2)特戊酰氯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100006
    Figure PCTCN2019106690-appb-100007
    (3)乙酰氯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100008
    (4)三氟乙酸酐酯化，反应式如下：
    Figure PCTCN2019106690-appb-100009
    (5)氯乙酰氯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100010
    (6)二氯乙酰氯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100011
    (7)氯甲酸甲酯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100012
    Figure PCTCN2019106690-appb-100013
    (8)氯甲酸乙酯酯化，反应式如下：
    Figure PCTCN2019106690-appb-100014
    (9)Boc酸酐酯化，反应式如下：
    Figure PCTCN2019106690-appb-100015
    (10)氯甲酸-2,2,2-三氯乙酯(Troc)酯化，反应式如下：
    Figure PCTCN2019106690-appb-100016
    (11)三甲基硅乙氧羰基氯(Teoc)酯化，反应式如下：
    Figure PCTCN2019106690-appb-100017
    (12)叔丁基二甲基氯硅烷醚化，反应式如下：
    Figure PCTCN2019106690-appb-100018
    (13)三异丙基氯甲硅烷醚化，反应式如下：
    Figure PCTCN2019106690-appb-100019
    (14)叔丁基二苯基氯硅烷醚化，反应式如下：
    Figure PCTCN2019106690-appb-100020
    (15)对甲氧苄基醚化PMB-(p-Methoxybenzyl)ether，反应式如下：
    Figure PCTCN2019106690-appb-100021
    (16)对甲氧苄基醚化PMB-(p-Methoxybenzyl)ether，反应式如下：
    Figure PCTCN2019106690-appb-100022
    (17)甲氧基乙氧基甲基氯醚化，反应式如下：
    Figure PCTCN2019106690-appb-100023
    (18)2-(三甲基硅烷基)乙氧甲基氯醚化，反应式如下：
    Figure PCTCN2019106690-appb-100024
    (19)四氢吡喃醚化，反应式如下：
    Figure PCTCN2019106690-appb-100025
    (20)1-乙氧基乙醇乙酸酯(EE)醚化，反应式如下：
    Figure PCTCN2019106690-appb-100026
    (21)烯丙基磺酰氯醚化，反应式如下：
    Figure PCTCN2019106690-appb-100027
    (22)对甲氧基苯酚醚化PMP-(p-Methoxyphenyl)ether，反应式如下：
    Figure PCTCN2019106690-appb-100028
  6. 根据权利要求2所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤二所述的三氟醋酸碘代Larotrectinib类似物的制备是将步骤一制得的活性羟基被保护的碘代Larotrectinib类似物前体(I-Larotrectinib)，与三氟乙酸或三氟乙酸酐、有机溶剂、氧化剂进行反应，使I被三氟醋酸根活化；
    所述的有机溶剂包括氯仿、二氯甲烷、乙腈、丙酮、过氧化叔丁醇中的一种或几种；
    所述的氧化剂包括脲-过氧化氢复合物、Oxone、2,2,6,6-四甲基哌啶-氧化物或mCPBA。
  7. 根据权利要求2所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤二所述的金刚烷取代的辅助酸为SPIAd，SPIAd与三氟醋酸碘代Larotrectinib类似物反应的条件为：SPIAd与碳酸钠溶液、MeCN、NaHCO 3和丙酮中的一种或几种在0℃混合，并控制混合液pH值为8～10，与三氟醋酸碘代Larotrectinib类似物在0℃连续搅拌反应1～10h得到标记前体。
  8. 根据权利要求2所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤二所述标记前体制备，具体包括以下方法：
    (1)制备标记前体I(III)-SPIAd-Bz-2-Larotrectinib或I(III)-SPIAd-Bz-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100029
    (2)制备标记前体I(III)-SPIAd-Piv-2-Larotrectinib或I(III)-SPIAd-Piv-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100030
    Figure PCTCN2019106690-appb-100031
    (3)制备标记前体I(III)-SPIAd-Ac-2-Larotrectinib或I(III)-SPIAd-Ac-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100032
    (4)制备标记前体I(III)-SPIAd-Tf-2-Larotrectinib或I(III)-SPIAd-Tf-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100033
    (5)制备标记前体I(III)-SPIAd-CAc-2-Larotrectinib或I(III)-SPIAd-CAc-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100034
    (6)制备标记前体I(III)-SPIAd-DCAc-2-Larotrectinib或I(III)-SPIAd-DCAc-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100035
    (7)制备标记前体I(III)-SPIAd-Moc-2-Larotrectinib或I(III)-SPIAd-Moc-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100036
    Figure PCTCN2019106690-appb-100037
    (8)制备标记前体I(III)-SPIAd-Eoc-2-Larotrectinib或I(III)-SPIAd-Eoc-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100038
    (9)制备标记前体I(III)-SPIAd-Boc-2-Larotrectinib或I(III)-SPIAd-Boc-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100039
    (10)制备标记前体I(III)-SPIAd-Troc-2-Larotrectinib或I(III)-SPIAd-Troc-2-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100040
    Figure PCTCN2019106690-appb-100041
    (11)制备标记前体I(III)-SPIAd-Teoc-2-Larotrectinib或I(III)-SPIAd-Teoc-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100042
    (12)制备标记前体I(III)-SPIAd-TBS-2-Larotrectinib或制备标记前体I(III)-SPIAd-TBS-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100043
    Figure PCTCN2019106690-appb-100044
    (13)制备标记前体I(III)-SPIAd-TBDPS-2-Larotrectinib或I(III)-SPIAd-TBDPS-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100045
    (14)制备标记前体I(III)-SPIAd-TIPS-2-Larotrectinib或I(III)-SPIAd-TIPS-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100046
    Figure PCTCN2019106690-appb-100047
    (15)制备标记前体I(III)-SPIAd-PMB-2-Larotrectinib或I(III)-SPIAd-PMB-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100048
    (16)制备标记前体I(III)-SPIAd-MOM-2-Larotrectinib或I(III)-SPIAd-MOM-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100049
    (17)制备标记前体I(III)-SPIAd-MEM-2-Larotrectinib或I(III)-SPIAd-MEM-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100050
    (18)制备标记前体I(III)-SPIAd-SEM-2-Larotrectinib或I(III)-SPIAd-SEM-2-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100051
    (19)制备标记前体I(III)-SPIAd-THP-2-Larotrectinib或I(III)-SPIAd-THP-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100052
    Figure PCTCN2019106690-appb-100053
    (20)制备标记前体I(III)-SPIAd-EE-2-Larotrectinib或I(III)-SPIAd-EE-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100054
    (21)制备标记前体I(III)-SPIAd-Als-2-Larotrectinib或I(III)-SPIAd-Als-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100055
    (22)制备标记前体I(III)-SPIAd-PMP-2-Larotrectinib或 I(III)-SPIAd-PMP-5-Larotrectinib，反应式如下：
    Figure PCTCN2019106690-appb-100056
  9. 根据权利要求2所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤三所述的氟-18放射性源通过以下方法获得：
    (1)制备[ 18F]氟化物靶水：[ 18F]氟化物靶水通过1 8O(p,n) 18F核反应生产，使用GE PETTrace回旋加速器，通过氮气压力将[ 18F]氟化物靶水递送到 18O-富集水的无菌铅保护热室；
    (2)QMA阴离子交换固相萃取盒(QMA)富集[ 18F]氟化物：将含有适量的[ 18F]氟化物的目标水的等分试样,在氮气流冲洗下，缓慢通过阴离子交换固相萃取盒(QMA)，将[ 18F]氟化物富集在QMA阴离子交换固相萃取盒(QMA)上，将 18O和其它不纯物分离洗脱除去，得到[ 18F]氟化物QMA阴离子交换固相萃取盒(QMA)的[ 18F]氟源；
    (3)洗脱QMA阴离子交换固相萃取盒(QMA)上富集的[ 18F]氟化物，得到[ 18F]氟化物季铵盐或无机盐溶液：使用冲洗液冲洗富集在QMA阴离子交换固相萃取盒(QMA)上的[ 18F]氟化物，将[ 18F]氟化物洗脱到用特氟隆衬垫隔膜密封的V形小瓶中，得到[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇溶液；
    (4)制备干燥的[ 18F]氟化物季铵盐或无机盐：将装有[ 18F]氟化物有机盐或无机盐的乙腈水溶液或乙腈或甲醇或乙醇溶液的特氟隆衬垫隔膜密封的V形小瓶加热至95-110℃，同时使氮气通过P 2O 5-Drierite TM柱干燥后吹扫V形小瓶，随后通过通气的小瓶排出尾气；当在小瓶中没有液体可见时，将其从热浴中取出，添加无水乙腈，并恢复加热直至干燥，将该步骤重复另外三次；然后将小 瓶在氮气流下，在室温下冷却，得到干燥的[ 18F]氟化物有机盐或无机盐。
  10. 根据权利要求9所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤(2)该阴离子交换固相萃取盒(QMA)事先使用NaHCO 3(aq)和水冲洗而预活化；
    步骤(3)所述的冲洗液为有机或无机碱溶解在体积比v/v7:3的乙腈和水、或乙腈、或甲醇、或乙醇中得到，所述的有机或无机碱包括四乙基碳酸氢铵；
    步骤(4)所述的[ 18F]氟化物有机盐或无机盐包括[ 18F]KF/K 2CO 3/K 2.2.2、[ 18F]KF/K 2C 2O 4/K 2.2.2、[ 18F]KF/KOTf、[ 18F]Et 4NF、[ 18F]Et 4NHCO 3、[ 18F]Et 4NOMs、[ 18F]Et 4NOTf，其放射性[ 18F]氟化物回收率，根据采用的洗脱工艺不同而有差异。
  11. 根据权利要求9所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤三所述的标记前体与氟-18放射性源取代反应：取装有干燥的[ 18F]氟化物有机盐或无机盐的V形小瓶，添加溶剂重新溶解，再添加标记前体，进行反应，得到[ 18F]-Larotrectinib未脱保护的标记物的粗品反应液。
  12. 根据权利要求9所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤三所述的脱保护通过以下方法实现：采用不添加或添加一定量的有机碱或无机碱或有机酸或无机酸至[ 18F]-Larotrectinib未脱保护的标记物的粗品反应液中，在加热条件下脱除羟基保护基，得到[ 18F]-Larotrectinib标记物的粗品反应液。
  13. 根据权利要求12所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，所述的[ 18F]-Larotrectinib标记物的粗品反应液还需要通过以下方法进行分离纯化：将[ 18F]-Larotrectinib标记物的粗品反应液通过采用半制备HPLC或Waters Sep-Pak C-18小柱纯化，并用溶剂淋洗进无菌真空瓶，60℃下氮气吹干20分钟，用盐水重新复配，其中含有100ul，25％的维生素C的水溶液，100ul，20％吐温80的乙醇溶液，即得[ 18F]-Larotrectinib标记物注射液。
  14. 根据权利要求2所述[ 18F]-标记Larotrectinib化合物的制备方法，其特征在于，步骤三由标记前体制备氟-18标记产物，具体包括以下方法：
    (1)由标记前体I(III)-SPIAd-Bz-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100057
    (2)由标记前体I(III)-SPIAd-TBS-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100058
    (3)由标记前体I(III)-SPIAd-SEM-2-Larotrectinib制备[ 18F]2--Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100059
    (4)由标记前体I(III)-SPIAd-TBDPS-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100060
    (5)由标记前体I(III)-SPIAd-TIPS-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100061
    Figure PCTCN2019106690-appb-100062
    (6)由标记前体I(III)-SPIAd-Teoc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100063
    (7)由标记前体I(III)-SPIAd-Piv-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100064
    Figure PCTCN2019106690-appb-100065
    (8)由标记前体I(III)-SPIAd-Ac-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100066
    (9)由标记前体I(III)-SPIAd-Tf-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100067
    (10)由标记前体I(III)-SPIAd-CAc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100068
    (11)由标记前体I(III)-SPIAd-DCAc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100069
    (12)由标记前体I(III)-SPIAd-Moc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100070
    (13)由标记前体I(III)-SPIAd-Eoc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100071
    (14)由标记前体I(III)-SPIAd-Boc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100072
    Figure PCTCN2019106690-appb-100073
    (15)由标记前体I(III)-SPIAd-Troc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100074
    (16)由标记前体I(III)-SPIAd-Troc-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100075
    (17)由标记前体I(III)-SPIAd-PMB-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100076
    (18)由标记前体I(III)-SPIAd-MOM-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100077
    (19)由标记前体I(III)-SPIAd-MEM-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100078
    (20)由标记前体I(III)-SPIAd-THP-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100079
    (21)由标记前体I(III)-SPIAd-EE-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100080
    (22)由标记前体I(III)-SPIAd-Als-2-Larotrectinib制备[ 18F]-2-Larotrectinib标记物，反应式如下：
    Figure PCTCN2019106690-appb-100081
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