Preparation method and intermediate of benzothiazole compound

Abstract

The invention discloses a preparation method and an intermediate of a benzothiazole compound. The invention specifically provides a preparation method of a compound (I), which comprises the following steps: reacting a compound (II) with fluoride in an organic solvent to obtain the compound (I), the fluoride is an inorganic fluoride or an organic fluorine compound; wherein R1 is represented by a formula (1), Boc, CH3, MOM or PMB; when the fluoride is inorganic fluoride, the reaction also comprises a phase transfer catalyst, and the reaction temperature is 70-120 DEG C; the molar ratio of the inorganic fluoride to the compound (II) is (2.5-30): 1; when the fluoride is organic fluoride, the reaction temperature is 50-70 DEG C; the molar ratio of the organic fluoride to the compound II is (1-30): 1. According to the preparation method disclosed by the invention, the compound (II) is used as a raw material, and the F0502B can be prepared by an in-vitro single-step reaction, so that the reaction time is greatly shortened, and a relatively high yield can be obtained. # imgabs0 #

Description

A preparation method of benzothiazole compound and intermediate thereof

[0001] This application claims priority to Chinese patent application No. 2023100160813, filed on January 5, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a preparation method of a benzothiazole compound and an intermediate thereof. Background Art

[0003] CN2019800317559 reports a class of styrylbenzothiazole derivatives that can be used as in vivo imaging agents for diagnosing Parkinson's disease (PD) or other degenerative disorders or central nervous system disorders. Specifically disclosed is compound F0502B that specifically binds to α-synuclein.

[0004] According to the records of CN2019800317559, compound 13 is first prepared from compound 12, and compound 13 is hydrolyzed in the body to obtain compound F0502B.

[0005] The reason for hydrolyzing compound 13 in vivo to obtain compound F0502B rather than further hydrolyzing compound 13 in vitro to prepare compound F0502B is that the further hydrolysis reaction of compound 13 in vitro is more difficult to occur, especially requiring a longer reaction time and a higher reaction temperature (for example, the reaction almost does not occur at room temperature overnight, and the reaction can only proceed by continuously increasing the temperature and reaction time during the process, until the temperature is increased to 80°C and the reaction takes more than 10 hours, and the reaction has a 70% conversion rate). During this process, compound 13 cannot always exist stably.

[0006] Therefore, the existing preparation method is to prepare compound 13 from compound 12, and compound 13 is hydrolyzed in vivo to obtain the active substance compound F0502B. The existing preparation method takes a long time to obtain compound F0502B, with low efficiency and yield, and is unstable during in vivo hydrolysis. Therefore, a method for efficiently preparing compound F0502B is needed.

[0007] Summary of the Invention

[0008] The present invention aims to provide a method for preparing a benzothiazole compound and its intermediates. The preparation method of the present invention uses compound II as a raw material and can achieve the preparation of F0502B in a single in vitro reaction, greatly shortening the reaction time and achieving a higher yield.

[0009] The present invention provides a method for preparing compound I, which comprises the following steps: reacting compound II with a fluoride in an organic solvent to obtain compound I; the fluoride is an inorganic fluoride or an organic fluoride;

[0010] Among them, R 1 for -Boc, -CH3, -MOM or -PMB;

[0011] When the fluoride is an inorganic fluoride, the reaction further comprises a phase transfer catalyst, the reaction temperature is 70-120° C.; the molar ratio of the inorganic fluoride to the compound II is (2.5-30):1;

[0012] When the fluoride is an organic fluoride, the reaction temperature is 50-70° C.; the molar ratio of the organic fluoride to the compound II is (1-30):1.

[0013] In one embodiment, when the fluoride is an inorganic fluoride, the reaction temperature is 80-100°C, for example, 85°C or 90°C.

[0014] In one embodiment, when the fluoride is an organic fluoride, the reaction temperature is 50-70°C, such as 55°C or 65°C.

[0015] In one embodiment, the organic fluoride is an organic nucleophilic fluorination agent, such as tetrabutylammonium fluoride.

[0016] In one embodiment, the inorganic fluoride is an alkali metal fluoride, such as KF and / or CsF.

[0017] In one embodiment, when the fluoride is an inorganic fluoride, the molar ratio of the inorganic fluoride to the compound II is (5-30):1, for example, 5:1, 10:1, 15:1, 20:1 or 30:1, and for example, 15:1.

[0018] In one embodiment, when the fluoride is an organic fluoride, the molar ratio of the organic fluoride to the compound II is (1.5-30):1, for example, 1.5:1, 5:1, 10:1, 15:1, 20:1 or 30:1, and for example, 1.5:1.

[0019] In a certain embodiment, when the fluoride is an inorganic fluoride, the phase transfer catalyst may be a conventional phase transfer catalyst in the art, such as Kryptofix 2.2.2 and / or [bmim][BF4].

[0020] In one embodiment, the molar ratio of the phase transfer catalyst to the compound II is (2-5):1, for example, 3:1.

[0021] In one embodiment, when the fluoride is an organic fluoride, the organic solvent is an ether solvent, such as tetrahydrofuran.

[0022] In one embodiment, when the fluoride is an inorganic fluoride, the organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride.

[0023] In one embodiment, the volume mass ratio of the organic solvent to the compound II is 10-100 ml / g, for example, 12 ml / g, 20 ml / g, 25 ml / g or 50 ml / g.

[0024] In one embodiment, the reaction is carried out under the protection of an inert gas, for example, nitrogen and / or helium.

[0025] In one embodiment, the reaction time is 0.1-20 h, for example, 0.3 h, 0.5 h, 1 h, 8 h or 15 h.

[0026] In a certain embodiment, when the fluoride is an organic fluoride, the preparation method includes the following steps: adding the organic fluoride to the compound II; for example, mixing the compound II with the organic solvent to obtain solution A, mixing the organic fluoride compound with the organic solvent to obtain solution B, and adding the solution B to the solution A.

[0027] In a certain embodiment, when the fluoride is an inorganic fluoride, the preparation method comprises the following steps: reacting a mixture of the compound II, an inorganic fluoride, a phase transfer catalyst and an organic solvent.

[0028] In a certain embodiment, the compound II is compound 8a or compound 8b:

[0029] In a certain scheme, when R 1 When -Boc or -PMB, the preparation method further comprises the following steps: in an organic solvent, in the presence of a base, compound IV undergoes a substitution reaction with TsCl to obtain compound II;

[0030] Among them, R 1 It is Boc or PMB.

[0031] In one embodiment, in the substitution reaction, the molar ratio of TsCl to compound IV is (1-10):1; for example, 3:1.

[0032] In a certain embodiment, in the substitution reaction, the base can be a conventional organic base in the art, such as triethylamine.

[0033] In one embodiment, in the substitution reaction, the organic solvent is a polar aprotic solvent, such as dichloromethane.

[0034] In a certain embodiment, in the substitution reaction, the temperature of the substitution reaction can be conventional in the art, for example, 20-50°C; for example, 35°C.

[0035] In one embodiment, the reaction time of the substitution reaction can be conventional in the art, until compound IV no longer reacts, for example, 2-24 h, and for example, 5 h.

[0036] The present invention also provides a benzothiazole compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the benzothiazole compound is Compound 8b, Compound 8c, Compound 8b-1, or Compound 10:

[0037] The present invention also provides a method for preparing a benzothiazole compound, which comprises the following steps: in an organic solvent, in the presence of a base, allowing compound IV to undergo a substitution reaction with TsCl to obtain compound II;

[0038] Among them, R 1 It is Boc or PMB.

[0039] In one embodiment, the conditions for the substitution reaction are as described in any of the previous embodiments.

[0040] The present invention also provides a method for preparing compound 8b-1, which comprises the following steps: the method for preparing compound 8b-1 comprises the following steps: at 70-120°C, in an organic solvent, in the presence of a phase transfer catalyst, reacting compound 8b with 18 F - Substitution reaction occurs to obtain compound 8b-1;

[0041] In one embodiment, the temperature of the substitution reaction is 90-110°C.

[0042] In one embodiment, the 18 F -It can be obtained by conventional methods in the art, for example, by capturing with a QMA column, or by capturing with a QMA light cartridge, or by capturing with a QMA light cartridge (Waters).

[0043] In a certain embodiment, the phase transfer catalyst may be a conventional phase transfer catalyst in the art, such as Kryptofix 2.2.2 / K2CO3.

[0044] In a certain embodiment, the Kryptofix 2.2.2 is in the form of a solution of Kryptofix 2.2.2, for example, Kryptofix 2.2.2 A CH3CN solution, for example, has a concentration of 10-20 mg / mL, and another example is 16.67 mg / mL.

[0045] In a certain embodiment, the K2CO3 is in the form of a K2CO3 solution, for example, in the form of an aqueous solution of K2CO3, for example, with a concentration of 10-50 mg / mL, for example 35 mg / mL.

[0046] In one embodiment, the molar ratio of the phase transfer catalyst to the compound 8b is (2-50):1, for example, 27:1.

[0047] In one embodiment, the organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride.

[0048] In one embodiment, the volume mass ratio of the organic solvent to the compound 8b is 10-1000 ml / g, for example, 500 ml / g.

[0049] In one embodiment, the reaction is carried out under the protection of an inert gas, for example, under the protection of nitrogen and / or helium, and for example, under the protection of nitrogen.

[0050] In one embodiment, the reaction time is 2 min-60 min, for example, 5 min.

[0051] In one embodiment, the preparation method comprises the following steps:

[0052] SS1. Capture with QMA column 18 F - ;

[0053] SS2. Use Kryptofix2.2.2 / K2CO3 to load the QMA column. 18 F - flushing into the reactor;

[0054] SS3 drying; for example, the drying is drying at 110 ℃; for another example, the drying is drying at 110 ℃ in an air bath and under a nitrogen flow;

[0055] SS4. 70-120 ° C, in the presence of a phase transfer catalyst, compound 8b and 18 F - Substitution reaction occurs to give compound 8b.

[0056] The present invention also provides a method for preparing compound I, comprising the following steps: reacting compound 9b with an inorganic fluoride in an organic solvent at 70-120° C. in the presence of a phase transfer catalyst to obtain compound I; the molar ratio of the inorganic fluoride to the compound 9b is (2.5-30):1;

[0057] In one embodiment, the reaction temperature is 80-100°C, for example 85°C or 90°C.

[0058] In one embodiment, the inorganic fluoride is an alkali metal fluoride, such as KF and / or CsF, and another example is KF.

[0059] In one embodiment, the molar ratio of the inorganic fluoride to the compound 9b is (5-30):1, for example, 5:1, 10:1, 15:1, 20:1 or 30:1, and for example, 15:1.

[0060] In a certain embodiment, the phase transfer catalyst may be a conventional phase transfer catalyst in the art, such as Kryptofix 2.2.2 and / or [bmim][BF4], and another example is Kryptofix 2.2.2.

[0061] In one embodiment, the molar ratio of the phase transfer catalyst to the compound 9b is (2-5):1, for example, 3:1.

[0062] In one embodiment, the organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride.

[0063] In one embodiment, the volume mass ratio of the organic solvent to the compound 9b is 10-100 ml / g, for example, 12 ml / g, 20 ml / g, 25 ml / g or 50 ml / g.

[0064] In one embodiment, the reaction is carried out under the protection of an inert gas, for example, nitrogen and / or helium.

[0065] In one embodiment, the reaction time is 0.1-20 h, for example, 0.3 h, 0.5 h, 1 h, 8 h or 15 h.

[0066] The present invention also provides a method for preparing compound III, which comprises the following steps: in an organic solvent at 70-90°C in the presence of a phase transfer catalyst, reacting compound 8a with 18 F - The reaction occurs to obtain compound III;

[0067] In one embodiment, the reaction temperature is 80-90°C, such as 85°C.

[0068] In one embodiment, the 18 F - It can be obtained by conventional methods in the art, for example, by capturing with a QMA column, or by capturing with a QMA light cartridge, or by capturing with a QMA light cartridge (Waters).

[0069] In a certain embodiment, the phase transfer catalyst may be a conventional phase transfer catalyst in the art, such as Kryptofix 2.2.2 / K2CO3.

[0070] In one embodiment, the Kryptofix 2.2.2 is in the form of a solution of Kryptofix 2.2.2, such as a CH3CN solution of Kryptofix 2.2.2, with a concentration of 10-20 mg / mL, and another example of 16.67 mg / mL.

[0071] In a certain embodiment, the K2CO3 is in the form of a K2CO3 solution, for example, in the form of an aqueous solution of K2CO3, for example, with a concentration of 10-50 mg / mL, for example 35 mg / mL.

[0072] In one embodiment, the molar ratio of the phase transfer catalyst to the compound 8a is (2-50):1, for example, 27:1.

[0073] In one embodiment, the organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride.

[0074] In one embodiment, the volume mass ratio of the organic solvent to the compound 8a is 10-1000 ml / g, for example, 800 ml / g.

[0075] In one embodiment, the reaction is carried out under inert gas protection, for example, under nitrogen and / or helium protection, for example, under helium protection; for example, under 6.0N helium protection.

[0076] In one embodiment, the reaction time is 0.1-2 h, for example 0.5 h.

[0077] In one embodiment, the preparation method comprises the following steps:

[0078] S1. Capture with QMA column 18 F - ;

[0079] S2. Use Kryptofix2.2.2 / K2CO3 to load the QMA column. 18 F - flushing into the reactor;

[0080] S3 drying; for example, the drying is 50-60 ℃, drying 5-10min, 80-90 ℃, drying 5-10min, the drying may be carried out under inert gas protection, for example, with 6.0NHe drying 5min, and then drying at 90 ℃ for another 5min;

[0081] S4. At 70-90°C, compound 8a is reacted with the substance obtained by drying in S3.

[0082] In one embodiment, the preparation method further comprises purification, which can be performed by HPLC. The HPLC column can be a C18 column, such as VP 250 / 16 NUCLEOSIL100-7 C18. The HPLC mobile phase can be CH3CN / H2O / TFA, 40:60:0.1 (v:v:v).

[0083] The present invention provides a method for preparing compound III, comprising the following steps: subjecting compound 8b-1 to a deprotection reaction in the presence of an acid at 60-110° C. to obtain compound III;

[0084] In one embodiment, the temperature of the deprotection reaction is 100-110°C.

[0085] In one embodiment, the molar ratio of the acid to the compound 8b-1 is conventional in the art, for example, (1-2000):1, and for example, 1075:1.

[0086] In a certain embodiment, the acid can be a conventional acid in the art, such as an inorganic acid, hydrochloric acid, or 3N hydrochloric acid solution.

[0087] In one embodiment, the deprotection reaction time is 2 min-60 min, for example, 5 min.

[0088] In one embodiment, the preparation method further comprises the preparation of compound 8b-1, which comprises the following steps: at 70-120°C, in an organic solvent, in the presence of a phase transfer catalyst, reacting compound 8b with 18 F - Substitution reaction occurs to obtain compound 8b-1;

[0089] In one embodiment, the substitution reaction is as described in any of the previous embodiments.

[0090] In one embodiment, the preparation method of compound III also includes a preparation method of compound 8b, which comprises the following steps: in an organic solvent, in the presence of a base, compound 10 undergoes a substitution reaction with TsCl to obtain compound 8b;

[0091] In one embodiment, in the substitution reaction, the molar ratio of TsCl to compound 10 is (1-10):1; for example, 3:1.

[0092] In one embodiment, in the substitution reaction, the base is a conventional organic base in the art, such as triethylamine.

[0093] In one embodiment, in the substitution reaction, the solvent is a polar aprotic solvent, such as dichloromethane.

[0094] In a certain embodiment, in the substitution reaction, the temperature of the substitution reaction can be conventional in the art, for example, 20-50°C; for example, 35°C.

[0095] In a certain embodiment, in the substitution reaction, the reaction time of the substitution reaction can be conventional in the art, until compound 10 no longer reacts, for example, 2-24 hours, and for example, 5 hours.

[0096] In the present invention, compound 8a or compound 8b and 18 During the F reaction, 18 F can be a conventional amount used in this type of reaction in the art.

[0097] In the present invention, Kryptofix2.2.2 is

[0098] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0099] The reagents and raw materials used in the present invention are commercially available.

[0100] The positive progress of the present invention is that the preparation method of the present invention can overcome the defects of the prior art in which compound 13 is prepared from compound 12, and compound 13 generates the active substance compound F0502B in vivo, and realizes the preparation of F0502B in vitro using compound II as the raw material through a single-step reaction in vitro, which greatly shortens the reaction time and can achieve a higher yield, while avoiding the instability of hydrolysis in vivo. DETAILED DESCRIPTION

[0101] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0102] Example 1

[0103] Under nitrogen, a mixture of compound 8a (20 mg, 1.0 eq), KF (4 mg, 2.5 eq), Kryptofix 2.2.2 (32.8 mg, 3 eq), and dry CH 3 CN (0.5 mL) was heated at 70° C. for 15 h. LCMS showed 38% of compound I in the reaction solution.

[0104] Example 2

[0105] The only difference from Example 1 is that the reaction temperature is 80° C. LCMS shows 53% of Compound I in the reaction solution.

[0106] Example 3

[0107] The only difference from Example 1 is that the reaction temperature is 90° C. and LCMS shows that there is 50% of Compound I in the reaction solution.

[0108] Example 4

[0109] Under nitrogen, a mixture of compound 8a (20 mg, 1.0 eq), KF (4 mg, 2.5 eq), Kryptofix 2.2.2 (32.8 mg, 3 eq) and dry CH 3 CN (0.5 mL) was heated at 80° C. for 8 h. LCMS showed 44% of compound I in the reaction solution.

[0110] Example 5

[0111] The only difference from Example 4 is that the amount of KF used is KF (8 mg, 5 eq). LCMS showed that there was 48% of Compound I in the reaction solution.

[0112] Example 6

[0113] The only difference from Example 4 is that the amount of KF used is KF (16 mg, 10 eq). LCMS showed that there was 60% of Compound I in the reaction solution.

[0114] Example 7

[0115] Under nitrogen, a mixture of compound 8a (10 mg, 1.0 eq), KF (17 mg, 20 eq), Kryptofix 2.2.2 (16 mg, 3 eq), and dry CH 3 CN (0.25 mL) was heated at 80° C. for 1 hour. LCMS showed 64% of compound I in the reaction solution.

[0116] Example 8

[0117] The only difference from Example 7 is that the amount of KF used is KF (25 mg, 30 eq). LCMS showed that there was 46% of Compound I in the reaction solution.

[0118] Example 9

[0119] Under nitrogen, a mixture of compound 8a (100 mg, 1.0 eq), KF (126 mg, 15 eq), Kryptofix 2.2.2 (164 mg, 3 eq) and dry CH 3 CN (1.2 mL) was heated at 80° C. for 0.5 h.

[0120] The reaction mixture was directly loaded onto a preparative HPLC (SunFire & PrepC 18 Purification was performed on a 5 μm column (19×150 mm) to obtain 20 mg of the product in a 30% yield. The column was eluted with a mobile phase of 38:62:0.1 v / v / v CH 3 CN / H 2 O / TFA at a flow rate of 15 mL / min.

[0121] Example 10

[0122] To a 10 mL Shrek tube, compound 8a (10 mg, 14.55 μmol, 1 eq), CsF (11.03 mg, 72.61 μmol, 5 eq), ACN (0.2 mL), and 1-butyl-3-methylimidazolium tetrafluoroborate (0.2 mL) were added, and the atmosphere was purged with nitrogen three times. Under nitrogen, the reaction solution was heated to 100°C. After 40 min, the reaction was complete. LCMS showed that the reaction solution contained 80.28% of compound I.

[0123] Example 11

[0124] To a 10 mL Shrek tube, compound 8a (10 mg, 14.55 μmol, 1 eq), CsF (11.03 mg, 72.61 μmol, 5 eq), DMSO (0.2 mL), and 1-butyl-3-methylimidazolium tetrafluoroborate (0.2 mL) were added, and the atmosphere was purged with nitrogen three times. The reaction mixture was heated to 100°C under nitrogen. After 20 min, LCMS showed that the reaction mixture contained 71.20% of compound I.

[0125] Example 12

[0126] At room temperature, compound 8a (10 mg, 14.55 μmol, 1.0 eq) was dissolved in THF (0.5 mL), and the nitrogen atmosphere was replaced three times. Under nitrogen protection, a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (21 μL, 21 μmol, 1.5 eq) was slowly added. The reaction mixture was heated to 55°C for 3 hours, then returned to room temperature and combined with the reaction mixture as in Example 13.

[0127] Example 13

[0128] At room temperature, compound 8a (50 mg, 72.78 μmol, 1 eq) was added to a 10 mL Shrek tube, and the nitrogen atmosphere was replaced three times. Under nitrogen protection, ultra-dry tetrahydrofuran (2.5 mL, 50 V) was added to the reaction solution, and then 1 M tetrabutylammonium fluoride (110 μL, 110 μmol, 1.5 eq) was slowly added dropwise to the reaction system. The reaction solution was heated to 55°C and reacted at this temperature for three hours. 1 M tetrabutylammonium fluoride (72.61 mL, 72.61 μmol, 1 eq) was added to the reaction system, and the reaction solution was continued at 55°C for one hour. The reaction solution was returned to room temperature and combined with the reaction solution of Example 12. The combined reaction solution was spin-dried and purified by column chromatography (eluent: ethyl acetate / n-heptane = 1 / 1) to obtain compound I in a yield of 15.06%. LCMS (ESI) m / z 465.0; 467.0 [M+H] + .

[0129] Example 14

[0130] Under nitrogen protection, a mixture of compound 8a (50 mg, 0.072 mmol, 1.0 eq), KF (63 mg, 1.1 mmol, 15 eq), Kryptofix 2.2.2 (82 mg, 0.22 mmol, 3 eq) and dry-CH 3 CN (0.6 mL) was heated at 80 ° C for 30 minutes. The reaction mixture was directly loaded on a preparative HPLC (SunFire & Prep C185 μm, 19 × 150 mm) for purification. The column was eluted with a mobile phase consisting of 38:62:0.1 v / v / v CH 3 CN / H 2 O / TFA at a flow rate of 15 mL / min. The desired elution fraction was collected and 1 / 2 of the eluate was lyophilized to obtain 8 mg of product in a yield of 23.68%.

[0131] 1 HNMR (400MHz, DMSO-d6): δ10.68 (s, 1H), 7.93 (s, 1H), 7.76-7.73 (m, 2H), 7.62 (dd, J=8.4Hz&2.0Hz, 1H), 7.44-7.39 ( m, 2H), 6.98 (d, J = 8.4Hz, 1H), 4.56-4.42 (m, 2H), 3.68-3.58 (m, 4H), 3.13 (t, J = 5.6Hz, 2H), 2.77 (s, 3H), 2.37 (s, 3H). 19 FNMR (376MHz, DMSO-d6): δ74.12 (s, 5F), 221.4 (s, 1F). MS (ESI) m / z464.9, 466.9[M+H] + .

[0132] Example 15

[0133] Under nitrogen, a mixture of compound 8b (20 mg, 0.027 mmol, 1.0 eq), KF (24 mg, 0.42 mmol, 15 eq), Kryptofix 2.2.2 (31 mg, 0.084 mmol, 3 eq), and dry CH3CN (0.5 mL) was heated at 80°C for 30 min. LCMS showed 26% of compound I in the reaction solution.

[0134] Example 16

[0135] The only difference from Example 15 was that the reaction temperature was changed from 80° C. to 90° C. LCMS showed that there was 30% of Compound I in the reaction solution.

[0136] Example 17

[0137] Under nitrogen, a mixture of compound 9b (20 mg, 0.032 mmol, 1.0 eq), KF (9.41 mg, 0.16 mmol, 5.0 eq), Kryptofix 2.2.2 (36 mg, 0.097 mmol, 3.0 eq) and dry CH 3 CN (0.5 mL) was heated at 80° C. for 30 min.

[0138] Example 18

[0139] Under nitrogen, a mixture of compound 9b (20 mg, 0.032 mmol, 1.0 eq), KF (18.8 mg, 0.32 mmol, 10.0 eq), Kryptofix 2.2.2 (36 mg, 0.097 mmol, 3.0 eq) and dry CH 3 CN (0.5 mL) was heated at 80° C. for 30 min.

[0140] The reaction mixtures from the two batches of reactions in Example 17 and Example 18 were combined and directly loaded onto a preparative HPLC column (SunFire & Prep C18 5μm, 19×150mm) for purification. The column was eluted with a mobile phase consisting of 38:62:0.1 (v / v / v) CH3CN / H2O / TFA at a flow rate of 15 mL / min. The desired fractions were collected to yield 3 mg of the title compound in a 10% yield (approximately 84% purity).

[0141] Example 19

[0142] 18 F - The reactor was captured by a QMA light cartridge (Waters) and flushed with a mixture of Kryptofix 2.2.2 (16.67 mg / mL in CH3CN solution, 0.9 mL) and K2CO3 (35 mg / mL in water, 0.1 mL). The mixture was dried with 6.0 N He at 60°C for 5 min and then dried at 90°C for another 5 min. Subsequently, 1.0 mg of compound 8a dissolved in 0.8 mL of anhydrous DMSO was added to the reactor and dried with 6.0 N He at 80°C. 18 F -The reaction was allowed to proceed for 30 min. After the reaction, the mixture was diluted with a mobile phase (40:60:0.1, CH3CN / H2O / TFA, volume ratio) and loaded onto a preparative HPLC (VP250 / 16 NUCLEOSIL 100-7C18) for purification, with the mobile phase eluting the column at a flow rate of 8 mL / min. The desired fractions were collected and diluted with 80 mL of sodium ascorbate solution (0.5% m / v). The diluted solution was then loaded into a C18 plus cartridge (Waters) and washed with 30 mL of sodium ascorbate solution (0.5%, m / v). The final radioactive product was eluted from the C18 plus cartridge using 2 mL of anhydrous ethanol. The yield was 3% (the yield was calculated as the amount of product radioactive F / the initial amount of radioactive F).

[0143] Example 20

[0144] (1) The [ 18 F]F - Use reservoir bottle 1 for K 2.2.2 / K2CO3 analytical solution was eluted into the reaction tube; the initial value of radioactive F was 1.6Ci;

[0145] (2) The resulting solution was evaporated to dryness in an air bath at 110°C under nitrogen flow;

[0146] (3) Under the same conditions, add anhydrous acetonitrile twice and repeat the operation of step (2) to obtain a dry nucleophilic reagent [ 18 F]KF / K 2.2.2 ;

[0147] (4) Fluorination reaction: After cooling, compound 8b (2 mg dissolved in 1 mL DMSO) was added to the reaction tube, mixed, and reacted at 110°C for 15 min.

[0148] (5) Deprotection reaction: Add 1.0 mL of 3N HCl solution and react at 100°C for 5 min to remove the Boc-protecting group on the O- to generate an -OH group;

[0149] (6) Neutralization reaction: Add 10 mL of 0.3 N NaOH solution into the reaction tube and mix the solution in the reaction tube to perform neutralization reaction;

[0150] (7) Purified product: 18 F]0502B was purified using a solid phase extraction C18 column. The reaction mixture was loaded onto the C18 column. After drying the C18 column, the column was washed with 20 mL of water. The crude product from the C18 column was then transferred to an HPLC transfer bottle using 2 mL of ethanol. The product was then purified by HPLC.

[0151] (8) The obtained product (160 mCi, yield 10%) was collected (the yield was calculated as the amount of radioactive F in the product / the initial amount of radioactive F, i.e., 160 mCi / 1.6 Ci = 10%).

[0152] Example 21:

[0153] At 0 ℃, to compound 10 (780mg, 1.39mmol, 1.0eq), Et3N (700mg, 6.93mmol, 5.0eq) in a mixture of dry DCM (30mL) solution, TsCl (791mg, 4.16mmol, 3.0eq) was added. Under nitrogen protection, the resulting mixture was heated at 25 ℃ for 16 hours. The reaction mixture was added with water (60mL) and extracted with DCM (50mL). The organic phase was washed with brine (30mL) and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (PE:EA=10:1 to 3:1) and preparative MPLC (C18 column, 5%-95%ACN / H2O) to give the product as a yellow solid (400mg, yield: 40%).

[0154] 1 H NMR (400MHz, DMSO-d6): δ8.16(s,1H),7.77-7.75(m,1H),7.72-7.63(m,4H),7.57-7.44(m,2H),7.42-7.40(m, 3H),4.41-4.09(m,2H),3.56-3.48(m,4H),3.02-3.01(m,2H),2.71(s,3H),2.38(s,3H),2.33(s,3H),1.51(s, 9H).MS(ESI)m / z 717.2 and 719.1[M+H] + .

[0155] Example 22

[0156] Compound 7 (800mg, 1.68mmol, 1.0eq), Boc The mixture of THF (16mL) solution of O (377mg, 1.68mmmol, 1.0eq) was heated at 70°C for 16 hours under nitrogen protection. The reaction mixture was added into water (30mL), and extracted with DCM (50mL), and the concentrated organic phase obtained a crude product. By silica gel column chromatography (PE: EA=10: 1 to 2: 1) and preparative MPLC (C18 post, 5%-95% ACN / H O) the crude product was purified to obtain the product (780mg, yield: 80%) as a yellow solid.

[0157] 1 H NMR (400MHz, DMSO-d6): δ8.16(s,1H),7.84-7.82(m,1H),7.76(s,2H),7.67-7.57(m,2H),7.42-7.40(d,J=8.4Hz,1H),4.55(t,J=5.6Hz,1 H),3.58(t,J=6.0Hz,2H),3.47-3.45(m,2H),3.41-3.39(m,2H),3.10(t,J=6.0Hz,2H),2.76(s,3H),2.37(s,3H),1.51(s,9H).MS(ESI)m / z 563.1 and 564.9[M+H] + .

[0158] Comparative Example 1:

[0159] Compound 8a (5 mg, 7.28 μmol, 1 eq), CsF (0.55 mg, 3.63 μmol, 0.5 eq), DMSO (0.1 mL), and 1-butyl-3-methylimidazolium tetrafluoroborate (0.1 mL) were added to a 10 mL Shrek tube, and the atmosphere was purged with nitrogen three times. Under nitrogen protection, the reaction solution was heated to 100°C and reacted at this temperature for 20 min. Compound I was not obtained.

[0160] Comparative Example 2:

[0161] To a 10 mL Shrek tube, ACN (0.2 mL), compound 8a (10 mg, 14.55 μmol, 1 eq), CsF (2.21 mg, 1 eq, 14.52 μmol), and 1-butyl-3-methylimidazolium tetrafluoroborate (0.2 mL) were added, and the atmosphere was purged with nitrogen three times. The reaction mixture was heated to 100°C under nitrogen and reacted for 40 min. Compound I was not obtained.

[0162] Comparative Example 3

[0163] A mixture of compound 8 (10 mg, 1.0 eq), NaOH (1.12 mg, 1.5 eq) and 1,4-dioxane (0.5 mL) / water (0.1 mL) was stirred at room temperature overnight, then stirred at 50°C for 2 h, and then at 60°C for an additional 2 h. TLC indicated that most of the starting material remained. Heating was continued at 80°C for 2 h, and LCMS indicated a 40% conversion rate. The reaction was further heated at 80°C for 10 h, and LCMS indicated 70% of compound I in the reaction solution.

Claims

1. A method for preparing compound I, characterized in that: The method comprises the following steps: in an organic solvent, compound II reacts with a fluoride to obtain compound I; the fluoride is an inorganic fluoride or an organic fluorine compound; Among them, R 1 for Boc, CH3, MOM or PMB; When the fluoride is an inorganic fluoride, the reaction further comprises a phase transfer catalyst, the reaction temperature is 70-120° C.; the molar ratio of the inorganic fluoride to the compound II is (2.5-30):1; When the fluoride is an organic fluoride, the reaction temperature is 50-70° C.; the molar ratio of the organic fluoride to the compound II is (1-30):

1.

2. The method for preparing Compound I according to claim 1, wherein The preparation method satisfies one or more of the following conditions: (1) When the fluoride is an inorganic fluoride, the reaction temperature is 80-100°C, for example, 85°C or 90°C; (2) When the fluoride is an organic fluoride, the reaction temperature is 50-70°C, for example, 55°C or 65°C; (3) the organic fluoride is an organic nucleophilic fluorination agent, such as tetrabutylammonium fluoride; and (4) The inorganic fluoride is an alkali metal fluoride, such as KF and / or CsF.

3. The method for preparing Compound I according to claim 1, wherein The preparation method satisfies one or more of the following conditions: (1) When the fluoride is an inorganic fluoride, the inorganic fluoride and the compound II The molar ratio is (5-30):1, for example, 5:1, 10:1, 15:1, 20:1 or 30:1, and for example, 15:1; (2) When the fluoride is an organic fluoride, the molar ratio of the organic fluoride to the compound II is (1.5-30):1, for example, 1.5:1, 5:1, 10:1, 15:1, 20:1 or 30:1, and for example, 1.5:1; (3) When the fluoride is an inorganic fluoride, the phase transfer catalyst is Kryptofix2.2.2 and / or [bmim][BF4]; (4) When the fluoride is an inorganic fluoride, the molar ratio of the phase transfer catalyst to the compound II is (2-5):1, for example, 3:1; (5) When the fluoride is an organic fluoride, the organic solvent is an ether solvent, such as tetrahydrofuran; (6) When the fluoride is an inorganic fluoride, the organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride; (7) The volume mass ratio of the organic solvent to the compound II is 10-100 ml / g, for example, 12 ml / g, 20 ml / g, 25 ml / g or 50 ml / g; (8) The reaction is carried out under the protection of an inert gas, for example, nitrogen and / or helium; (9) The reaction time is 0.1-20 h, for example, 0.3 h, 0.5 h, 1 h, 8 h or 15 h; (10) When the fluoride is an organic fluoride, the preparation method comprises the following steps: adding the organic fluoride to the compound II; for example, the compound II is mixed with the organic solvent to obtain a solution A, the organic fluoride is mixed with the organic solvent to obtain a solution B, and the solution B is added to the solution A; (11) When the fluoride is an inorganic fluoride, the preparation method comprises the following steps: reacting a mixture of the compound II, an inorganic fluoride, a phase transfer catalyst and an organic solvent; and (12) Compound II is Compound 8a or Compound 8b:

4. The method for preparing Compound I according to claim 1, wherein When R 1 When Boc or PMB, the preparation method is also The method comprises the following steps: in an organic solvent, in the presence of a base, compound IV undergoes a substitution reaction with TsCl to obtain compound II; Among them, R 1 It is Boc or PMB.

5. The method for preparing Compound I according to claim 4, wherein: The substitution reaction satisfies one or more of the following conditions: (1) The molar ratio of TsCl to compound IV is (1-10):1; for example, 3:1; (2) The base is an organic base, such as triethylamine; (3) The organic solvent is a polar aprotic solvent, such as dichloromethane; (4) the temperature of the substitution reaction is 20-50°C; for example, 35°C; and (5) The reaction time of the substitution reaction is 2-24 hours, for example, 5 hours.

6. A benzothiazole compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the benzothiazole compound is Compound 8b, Compound 8c, Compound 8b-1, or Compound 10:

7. A method for preparing a benzothiazole compound, characterized in that: It includes the following steps: In an organic solvent, in the presence of a base, compound IV undergoes a substitution reaction with TsCl to obtain compound II; Among them, R 1 It is Boc or PMB.

8. The method for preparing a benzothiazole compound according to claim 7, wherein: The conditions for the substitution reaction are as described in claim 5.

9. A method for preparing compound 8b-1, characterized in that: It includes the following steps: The preparation method of the compound 8b-1 comprises the following steps: at 70-120° C., in an organic solvent, in the presence of a phase transfer catalyst, reacting compound 8b with 18 F - Substitution reaction occurs to obtain compound 8b-1; 10. The method for preparing compound 8b-1 according to claim 9, wherein The substitution reaction satisfies one or more of the following conditions: (1) The temperature of the substitution reaction is 90-110°C; (2) 18 F - Captured by a QMA column, for example, by a QMA light cartridge, for example, by a QMA light cartridge, Waters; (3) The phase transfer catalyst is Kryptofix2.2.2 / K2CO3; (4) The molar ratio of the phase transfer catalyst to the compound 8b is (2-50):1, for example, 27:1; (5) The organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride; (6) The volume mass ratio of the organic solvent to the compound 8b is 10-1000 ml / g, for example, 500 ml / g; (7) The reaction is carried out under the protection of an inert gas, for example, nitrogen and / or helium. and (8) The reaction time is 2 min to 60 min, for example, 5 min.

11. The method for preparing compound 8b-1 according to claim 10, wherein The substitution reaction satisfies one or more of the following conditions: (1) The Kryptofix 2.2.2 is in the form of a solution of Kryptofix 2.2.2, for example, a CH3CN solution of Kryptofix 2.2.2, and for example, a concentration of 10-20 mg / mL, and for example, 16.67 mg / mL; (2) The K2CO3 is in the form of a K2CO3 solution, for example, in the form of an aqueous solution of K2CO3, for example, with a concentration of 10-50 mg / mL, for example, 35 mg / mL; (3) The preparation method comprises the following steps: SS1. Capture with QMA column 18 F - ; SS2. Use Kryptofix2.2.2 / K2CO3 to load the QMA column. 18 F - flushing into the reactor; SS3 drying; for example, the drying is drying at 110 ℃; for another example, the drying is drying at 110 ℃ in an air bath and under a nitrogen flow; SS4. 70-120 ° C, in the presence of a phase transfer catalyst, compound 8b and 18 F - A substitution reaction occurs to obtain compound 8b-1.

12. A method for preparing compound I, characterized in that: It includes the following steps: Compound 9b is reacted with an inorganic fluoride in an organic solvent at 70-120° C. in the presence of a phase transfer catalyst to obtain compound I; the molar ratio of the inorganic fluoride to the compound 9b is (2.5-30):1; 13. The method for preparing Compound I according to claim 12, wherein: The preparation method satisfies one or more of the following conditions: (1) The reaction temperature is 80-100°C, for example, 85°C or 90°C; (2) The inorganic fluoride is an alkali metal fluoride, such as KF and / or CsF, and another example is KF; (3) The molar ratio of the inorganic fluoride to the compound 9b is (5-30):1, for example, 5:1, 10:1, 15:1, 20:1 or 30:1, and for example, 15:1; (4) The phase transfer catalyst is Kryptofix 2.2.2 and / or [bmim][BF4], for example Kryptofix 2.2.2; (5) The molar ratio of the phase transfer catalyst to the compound 9b is (2-5):1, for example, 3:1; (6) The organic solvent is a nitrile solvent and / or a sulfoxide solvent, for example, a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, and for example, the sulfoxide solvent is thionyl chloride; (7) The volume mass ratio of the organic solvent to the compound 9b is 10-100 ml / g, for example, 12 ml / g, 20 ml / g, 25 ml / g or 50 ml / g; (8) the reaction is carried out under the protection of an inert gas, for example, nitrogen and / or helium; and (9) The reaction time is 0.1-20 h, for example, 0.3 h, 0.5 h, 1 h, 8 h or 15 h.

14. A method for preparing compound III, characterized in that: The method comprises the following steps: in an organic solvent at 70-90°C, in the presence of a phase transfer catalyst, reacting compound 8a with 18 F - The reaction occurs to obtain compound III; 15. The method for preparing compound III according to claim 14, wherein: The preparation method satisfies one or more of the following conditions: (1) The reaction temperature is 80-90°C, for example 85°C; (2) 18 F - Captured by a QMA column, for example, by a QMA light cartridge, for example, by a QMA light cartridge, Waters; (3) The phase transfer catalyst is Kryptofix2.2.2 / K2CO3; (4) The molar ratio of the phase transfer catalyst to the compound 8a is (2-50):1, for example, 27:1; (5) The organic solvent is a nitrile solvent and / or a sulfoxide solvent, preferably a sulfoxide solvent, for example, the nitrile solvent is acetonitrile, for example, the sulfoxide solvent is thionyl chloride; (6) The volume mass ratio of the organic solvent to the compound 8a is 10-1000 ml / g, for example, 800 ml / g; (7) the reaction is carried out under inert gas protection, for example, under nitrogen and / or helium protection, for example, under helium protection; for example, under 6.0N helium protection; and (8) The reaction time is 0.1-2 hours, for example 0.5 hours.

16. The method for preparing compound III according to claim 15, wherein: The preparation method satisfies one or more of the following conditions: (1) The Kryptofix 2.2.2 is in the form of a solution of Kryptofix 2.2.2, for example, a CH3CN solution of Kryptofix 2.2.2, for example, with a concentration of 10-20 mg / mL, for example 16.67 mg / mL; (2) The K2CO3 is in the form of a K2CO3 solution, for example, in the form of an aqueous solution of K2CO3, for example, with a concentration of 10-50 mg / mL, and further for example 35 mg / mL; (3) The preparation method comprises the following steps: S1. Capture with QMA column 18 F - ; S2. Use Kryptofix2.2.2 / K2CO3 to load the QMA column. 18 F - flushing into the reactor; S3 drying; for example, the drying is 50-60 ℃, drying 5-10min, 80-90 ℃, drying 5-10min, the drying may be carried out under inert gas protection, for example, with 6.0NHe drying 5min, and then drying at 90 ℃ for another 5min; S4. 70-90°C, reacting compound 8a with the dried product obtained in S3; and (4) The preparation method further includes purification, and the purification can be performed using HPLC; the HPLC chromatographic column can be a C18 column, for example, VP 250 / 16 NUCLEOSIL100-7 C18; the HPLC mobile phase can be CH3CN / H2O / TFA, 40:60:0.1 (v:v:v).

17. A method for preparing compound III, characterized in that: It includes the following steps: At 60-110°C, compound 8b-1 undergoes a deprotection reaction in the presence of an acid to obtain compound III; 18. The method for preparing compound III according to claim 17, wherein: The preparation method satisfies one or more of the following conditions: (1) The temperature of the deprotection reaction is 100-110°C; (2) The molar ratio of the acid to the compound 8b-1 is (1-2000):1, for example, 1075:1; (3) the acid is an inorganic acid, such as hydrochloric acid, and another example is 3N hydrochloric acid solution; and (4) The deprotection reaction time is 2 min-60 min, for example, 5 min.

19. The method for preparing compound III according to claim 17, wherein: The preparation method also includes the preparation of compound 8b-1, which comprises the following steps: at 70-120° C., in an organic solvent, in the presence of a phase transfer catalyst, reacting compound 8b with 18 F - Substitution reaction occurs to obtain compound 8b-1; The substitution reaction may be as described in claim 10 or 11.

20. The method for preparing compound III according to claim 19, wherein: The preparation method also includes a preparation method of compound 8b, which comprises the following steps: in an organic solvent, in the presence of a base, compound 10 undergoes a substitution reaction with TsCl to obtain compound 8b; Preferably, the substitution reaction satisfies one or more of the following conditions: (1) The molar ratio of TsCl to compound 10 is (1-10):1; for example, 3:1; (2) The base is an organic base, such as triethylamine; (3) The solvent is a polar aprotic solvent, such as dichloromethane; (4) the temperature of the substitution reaction is 20-50°C; for example, 35°C; and (5) The reaction time of the substitution reaction is 2-24 hours, for example, 5 hours.

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