A method for preparing an azide compound

Abstract

The present invention discloses a method for preparing an azide compound. The present invention provides a method for preparing an azide compound as shown in Formula 3, comprising the following steps: in an organic solvent, in the presence of an alkali metal carbonate and a copper salt, subjecting an amine compound as shown in Formula 2 to an azide reagent for an azidation reaction to obtain an azide compound as shown in Formula 3; the azide reagent is 1H-imidazolesulfonyl azide or a salt thereof; wherein C 13 H 27 This method is simple to synthesize, has mild conditions, reduces post-processing operations, and can be used for industrial production. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a method for preparing an azide compound. Background Art

[0002] KRN7000 is an α-galactosylceramide (α-GalCer) isolated from sponge tissue in the waters off Okinawa, Japan, by Chin et al. in 1993. It has a wide range of biological activities, including anti-tumor, anti-tuberculosis, anti-fungal, and anti-inflammatory properties, as well as therapeutic effects on autoimmune diseases (such as systemic lupus erythematosus and diabetes).

[0003]

[0004] In the process of synthesizing KRN7000, the amino group in the phytosphingosine structure is generally azidated to ensure the yield of the glycosylation reaction, because the amino group in phytosphingosine will form a hydrogen bond with the hydrogen in the terminal hydroxyl group, hindering the reaction.

[0005]

[0006] There are already reports on the synthesis of this intermediate, but the terminal hydroxyl protecting groups are different. For example, Akimoto et al. [1] synthesized an analogue of this intermediate (with a different carbon chain length) in 1993. They used methanesulfonyl chloride and sodium azide to introduce the azide group in two steps, and used triphenyl as the terminal hydroxyl protecting group, with an overall yield of 30.9%. ([1] Akimoto K, Natori T, Morita M. Synthesis and stereochemistry of agelasphin-9b [J]. Tetrahedron Letters, 1993, 34 (35): 5593-5596.)

[0007] Huang, Yin-Cheng et al. [2] used phytosphingosine as raw material and used tert-butyl dimethyl (TBDMS) as terminal hydroxyl protecting group. After one step of TfN3 preparation (72% [3], and 4 steps of protection and deprotection process, 1 was obtained with a total yield of 41%. Trityl as terminal hydroxyl protecting group has poor removal effect and low yield. When tert-butyl dimethyl is used as terminal protecting group, it is easy to protect the other two hydroxyl groups in the phytosphingosine structure. The highly toxic reagent sodium azide was used to prepare TfN3 for diazotization of amino group, and the column chromatography operation was complicated. ([2] Huang YC, Li-Wu C, Chang KS, et al. Synthesis of Amino Core Compounds of Galactosyl Phytosyl Ceramide Analogs for Developing iNKT-Cell Inducers [J]. Molecules, 2012, 17 (3). [3] Oh KI, Lee JH, Joo C, et al. Synthesis of Amino Core Compounds of Galactosyl Phytosyl Ceramide Analogs for Developing iNKT-Cell Inducers [J]. Molecules, 2012, 17 (3). [3] Oh KI, Lee JH, Joo C, et al. al.Beta-azidoalanine as an IR probe:application to amyloid Abeta(16-22)aggregation.[J].Journal of Physical Chemistry B,2008,112(33):10352-10357.)

[0008] The diazo transfer reaction using trifluoromethanesulfonyl azide (CF3SO2N3, also known as TfN3) has become a common method for preparing organic azides from primary amines and is compatible with many functional groups. However, the diazo transfer reaction of TfN3 has several problems: first, the reaction requires an excess of TfN3 and the reaction time is long; second, the preparation of TfN3 requires the use of excess sodium azide under acidic conditions, which brings toxicity and explosion risks.

[0009] Veerapen et al. [4] used tert-butyldiphenylsilyl (TBDPS) as a terminal hydroxyl protecting group and obtained 1 with a total yield of 46.8% after the same 5-step reaction. The total yield of this route was significantly improved, but the highly toxic reagent sodium azide was also used to prepare TfN3 for diazotization of the amino group. The column chromatography operation was complicated, and pyridine was used as a solvent when the TBDPS protecting group was added, which had a relatively high odor toxicity ([4] Veerapen N, Brigl M, Garg S, et al. Synthesis and biological activity of α-galactosyl ceramide KRN7000 and galactosyl(α1→2)galactosyl ceramide [J]. Bioorganic & Medicinal Chemistry Letters, 2009, 19 (15): 4288-4291.). Summary of the Invention

[0010] The present invention addresses the technical problem of using sodium azide, a highly toxic reagent, to prepare TfN3 for the diazotization of amino groups, and employs pyridine, a solvent with a high odor toxicity. This method provides a method for preparing an azide compound. This method utilizes a simple synthetic method to obtain compound 1, which serves as a key intermediate for obtaining KRN7000. This method facilitates simple synthesis under mild conditions, employs a one-pot reaction followed by a continuous batching strategy to shorten reaction time and reduce post-processing, enabling industrial production.

[0011] The present invention provides a method for preparing an azide compound as shown in Formula 3, comprising the following steps: in an organic solvent, in the presence of an alkali metal carbonate and a copper salt, subjecting an amine compound as shown in Formula 2 and an azide reagent to an azidation reaction to obtain an azide compound as shown in Formula 3; the azide reagent is 1H-imidazolesulfonyl azide or a salt thereof;

[0012]

[0013] Among them, C 13 H 27 It is n-tridecyl.

[0014] In the azide reaction, the organic solvent is a conventional solvent for this type of reaction in the art, and can be an alcohol solvent and / or an ether solvent.

[0015] In the azide reaction, the alcohol solvent may be methanol.

[0016] In the azide reaction, the ether solvent may be tetrahydrofuran.

[0017] In the azide reaction, the organic solvent may be an alcohol solvent or an ether solvent, and the volume ratio of the alcohol solvent to the ether solvent may be 1:3.

[0018] In the azide reaction, the mass volume ratio of the amine compound represented by Formula 2 to the organic solvent can be 0.04 g / mL-0.06 g / mL, or 0.049 g / mL.

[0019] In the azide reaction, the alkali metal carbonate may be potassium carbonate.

[0020] In the azide reaction, the molar ratio of the alkali metal carbonate to the amine compound shown in Formula 2 can be (1-2):1, or 1.5:1.

[0021] In the azide reaction, the copper salt may be copper sulfate pentahydrate.

[0022] In the azide reaction, the molar ratio of the copper salt to the amine compound shown in Formula 2 can be (0-1):1, or can be 0.01:1.

[0023] In the azide reaction, the salt of 1H-imidazolesulfonyl azide can be 1H-imidazolesulfonyl azide hydrochloride.

[0024] In the azide reaction, the molar ratio of the azide reagent to the amine compound shown in Formula 2 can be (1-2):1, or 1.1:1.

[0025] In the azide reaction, the reaction conditions may be as follows: the organic solvent is an alcohol solvent and an ether solvent, the alcohol solvent is methanol, the ether solvent is tetrahydrofuran, and the volume ratio of the alcohol solvent to the ether solvent is 1:3; the mass volume ratio of the amine compound represented by Formula 2 to the organic solvent is 0.049 g / mL; the alkali metal carbonate is potassium carbonate, and the molar ratio of the alkali metal carbonate to the amine compound represented by Formula 2 is 1.5:1; the copper salt is copper sulfate pentahydrate, and the molar ratio of the copper salt to the amine compound represented by Formula 2 is 0.01:1; the salt of 1H-imidazolesulfonyl azide is 1H-imidazolesulfonyl azide hydrochloride, and the molar ratio of the azide reagent to the amine compound represented by Formula 2 is 1.1:1.

[0026] The temperature of the azide reaction is a conventional temperature for such reactions in the art, such as room temperature (25°C).

[0027] The progress of the azide reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally determined as the disappearance or cessation of reaction of the amine compound represented by Formula 2. The reaction time can be 1-10 hours, or even 4-5 hours.

[0028] The azide reaction may further include post-treatment, and the post-treatment operation may be conventional post-treatment operations for such reactions in the art. For example, the post-treatment operation is as follows: after the azide reaction is completed, the reaction solution is filtered, the filtrate is concentrated, slurried, filtered, dissolved, recrystallized, and then filtered. The filter cake is dried to obtain the azide compound shown in Formula 3.

[0029] The beating is preferably performed with petroleum ether, the dissolving is preferably performed with methanol, and the recrystallization is preferably performed at -20°C.

[0030] The present invention also provides a method for preparing the compound shown in Formula 5, which comprises the following steps:

[0031] (1) In an organic solvent, in the presence of N2, in the presence of a base and a pyridine catalyst, TBDPSCl is reacted with an azide compound as shown in Formula 3 to perform a primary alcohol protection reaction to obtain a compound as shown in Formula 4;

[0032] (2) In the reaction solution of step (1), in the presence of pyridine, a secondary alcohol protection reaction is carried out on benzoyl chloride and the compound shown in Formula 4 to obtain a compound shown in Formula 5;

[0033]

[0034] Among them, C 13 H 27 It is n-tridecyl.

[0035] In step (1), the organic solvent is a conventional solvent for this type of reaction in the art. The organic solvent may be a halogenated hydrocarbon solvent.

[0036] In step (1), the halogenated hydrocarbon solvent may be dichloromethane or super dry dichloromethane.

[0037] In step (1), the mass volume ratio of the azide compound represented by Formula 3 to the organic solvent can be 0.04 g / mL-0.06 g / mL, or 0.052 g / mL.

[0038] In step (1), the base may be imidazole.

[0039] In step (1), the equivalent ratio of the base to the azide compound shown in Formula 3 can be (2.5-3):1, or can be 3:1.

[0040] In step (1), the pyridine catalyst may be DMAP.

[0041] In step (1), the equivalent ratio of the pyridine catalyst to the azide compound shown in Formula 3 can be (0-0.2):1, or can be 0.1:1.

[0042] In step (1), the equivalent ratio of TBDPSCl to the azide compound shown in Formula 3 can be (1.0-1.2):1, or can be 1.1:1.

[0043] In step (1), the temperature for the protection reaction of the primary alcohol is a conventional temperature for such reactions in the art, such as room temperature (25°C).

[0044] In step (1), the progress of the protection reaction of the primary alcohol can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the azide compound shown in Formula 3 disappears or no longer reacts.

[0045] In step (1), the protection reaction of the primary alcohol may be carried out under the following reaction conditions: in the presence of N2, the organic solvent is dichloromethane, the mass volume ratio of the azide compound shown in Formula 3 to the organic solvent is 0.052 g / mL, the base is imidazole, the equivalent ratio of the base to the azide compound shown in Formula 3 is 3:1, the pyridine catalyst is DMAP, the equivalent ratio of the pyridine catalyst to the azide compound shown in Formula 3 is 0.1:1, and the equivalent ratio of TBDPSCl to the azide compound shown in Formula 3 is 1.1:1.

[0046] Preferably, the reaction solution is directly used for the protection reaction of the secondary alcohol.

[0047] In step (2), the equivalent ratio of pyridine to the azide compound shown in Formula 3 can be 12:1.

[0048] In step (2), the equivalent ratio of the benzoyl chloride to the azide compound shown in Formula 3 may be 6:1.

[0049] In step (2), the temperature of the protection reaction of the secondary alcohol is a conventional temperature for such reactions in the art, such as room temperature (25°C).

[0050] The method for preparing the compound of Formula 5 may further comprise post-treatment, and the post-treatment operations may be conventional post-treatment operations in such preparation methods in the art. For example, the post-treatment operations may be as follows: quenching, concentration, extraction, water washing, drying, and then concentration.

[0051] The quenching method is preferably methanol. The extraction method is preferably petroleum ether. The washing method is preferably saturated NaHCO3 solution or saturated brine. The drying method is preferably drying over anhydrous sodium sulfate.

[0052] In the protection reaction of the secondary alcohol, the reaction conditions can be as follows: the equivalent ratio of the pyridine to the azide compound shown in Formula 3 is 12:1, and the equivalent ratio of the benzoyl chloride to the azide compound shown in Formula 3 is 6:1.

[0053] In the method for preparing the compound as shown in Formula 5, the method for preparing the compound as shown in Formula 5 may further include the following steps: preparing the azide compound as shown in Formula 3 according to the above-mentioned azide reaction.

[0054] The present invention also provides a method for preparing a compound as shown in Formula 1, comprising the following steps: in an organic solvent, subjecting a compound as shown in Formula 5 and a hydrogen fluoride pyridine solution to a deprotection reaction as shown below to obtain Compound 1;

[0055]

[0056] Among them, C 13 H 27 It is n-tridecyl.

[0057] In the deprotection reaction, the organic solvent is a conventional solvent for this type of reaction in the art, and can be an ether solvent.

[0058] In the deprotection reaction, the ether solvent may be tetrahydrofuran.

[0059] In the deprotection reaction, the amount of the organic solvent used is the conventional amount used in experiments in this field, which does not affect the reaction. For example, the mass volume ratio of the compound shown in Formula 5 to the organic solvent can be 0.045 g / mL-0.05 g / mL, or can be 0.046 g / mL.

[0060] In the deprotection reaction, the equivalent ratio of the hydrogen fluoride pyridine solution to the compound represented by Formula 5 can be (10-30):1, or can be 20:1.

[0061] In the deprotection reaction, the hydrogen fluoride pyridine solution is a 70% hydrogen fluoride pyridine solution.

[0062] In the deprotection reaction, it is preferably carried out in a fluorination bottle.

[0063] The deprotection reaction preferably comprises the following steps: adding a hydrogen fluoride pyridine solution to a solution formed by the compound represented by Formula 5 and the organic solvent, and performing the deprotection reaction. The adding method is preferably dropwise addition.

[0064] In the deprotection reaction, the reaction conditions can be as follows: the reaction is carried out in a fluorination bottle, the organic solvent is an ether solvent, the mass volume ratio of the compound represented by Formula 5 to the organic solvent is 0.046 g / mL, and the equivalent ratio of the hydrogen fluoride pyridine solution to the compound represented by Formula 5 is 20:1.

[0065] The deprotection reaction temperature can be a conventional temperature for such reactions in the art, such as 0°C.

[0066] The progress of the deprotection reaction can be monitored using conventional monitoring methods in the art (eg, TLC, HPLC, or NMR). The reaction endpoint is generally determined when the compound of Formula 5 disappears or ceases to react.

[0067] The deprotection reaction may further include post-treatment, which may include the following steps: quenching, extraction, washing, drying, concentration and purification to obtain the compound 1.

[0068] The quenching can be a conventional quenching method in this type of reaction in the art, for example, quenching the reaction using a saturated NaHCO solution until the water layer is neutral. The extraction can be a conventional extraction method in this type of reaction in the art, for example, using a solvent (such as ethyl acetate) to extract. The washing can be a conventional washing method in this type of reaction in the art, for example, using the solvent (such as saturated brine and water) to wash. The drying can be a conventional drying method in this type of reaction in the art, for example, using anhydrous sodium sulfate drying for more than 3h. The concentration can be a conventional concentration method in this type of reaction in the art, for example, concentrating under reduced pressure. The purification can be a conventional purification method in this type of compound in the art, for example, column chromatography.

[0069] In the preparation method of the compound shown in Formula 1, the preparation method of the compound shown in Formula 1 may further include the following steps: preparing the compound shown in Formula 4 according to the above-mentioned protection reaction of the primary alcohol and preparing the compound shown in Formula 5 according to the above-mentioned protection reaction of the secondary alcohol.

[0070] In the method for preparing the compound as shown in Formula 1, the method for preparing the compound as shown in Formula 1 may further include the following steps: according to the above-mentioned azide reaction, preparing the azide compound as shown in Formula 3; according to the above-mentioned protection reaction of the primary alcohol, preparing the compound as shown in Formula 4; and according to the above-mentioned protection reaction of the secondary alcohol, preparing the compound as shown in Formula 5.

[0071] 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.

[0072] The reagents and raw materials used in the present invention are commercially available.

[0073] The positive progress effect of the present invention is:

[0074] (1) The highly efficient and safe azide reagent 1H-imidazolesulfonyl azide hydrochloride is used to carry out the aminodiazotization reaction, which greatly shortens the reaction time; (2) The present invention greatly reduces the reaction treatment time and saves solvents through the one-pot method and continuous injection strategy, and adopts recrystallization to eliminate a large number of complicated column chromatography operations, thereby greatly improving the total yield (61.15%), which is 14.35% higher than the original literature; (3) The conditions for the TBDPS protecting group protection reaction are optimized, and the amount of pyridine is reduced by 80%, while shortening the reaction time; (4) After the process optimization of the route, the 10-gram process is currently stable. DETAILED DESCRIPTION

[0075] 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.

[0076] The abbreviations used in the present invention are explained as follows:

[0077] DMAP—4-dimethylaminopyridine

[0078] TBDPSCl—tert-butyldiphenylsilyl chloride

[0079] MeOH—methanol

[0080] THF—tetrahydrofuran

[0081] EA—ethyl acetate

[0082] TfN3—trifluoromethanesulfonyl azide

[0083] DMF—N,N-dimethylformamide

[0084] Example 1

[0085]

[0086] At room temperature (25°C), compound 2 (9.8g, 1eq) was dissolved in THF:MeOH = 3:1 (200ml). 1H-imidazolesulfonyl azide hydrochloride (7.1g, 1.1eq) was added. After stirring until the solution was clear, potassium carbonate (4.8g, 1.5eq) and copper sulfate pentahydrate (47mg, 0.01eq) were added. After 4 hours, the reaction was complete as monitored by TLC. The reaction solution was filtered to remove solid insoluble impurities. The filtrate was concentrated to dryness, slurried with petroleum ether to remove low-polarity impurities, and filtered. The filter cake was dissolved in an appropriate amount of methanol, recrystallized at -20°C, and filtered. The filter cake was dried to obtain compound 3 with a yield of 91% and a purity of 99.28%. 1 H NMR (400MHz, CDCl3): δ4.02(dd,J=11.6,5.2Hz,1H),3.92(dd,J=11.6,4.4Hz,1H),3.82(m,1 H),3.78(m,1H),3.69(m,1H),1.64-1.54(m,3H),1.46-1.28(m,23H),0.91(t,J=6.8Hz,3H). 13 C NMR (100MHz, CDCl3): δ74.8,72.6,63.4,62.0,32.0,31.9,29.6,29.5,29.3,25.7,22.6,14.0.

[0087] Example 2:

[0088]

[0089] At room temperature (25°C) under N2 protection, compound 3 (5.2 g, 1 eq) prepared in Example 1 was dissolved in ultra-dry dichloromethane (100 ml). Imidazole (3.1 g, 3 eq) and DMAP (185 mg, 0.1 eq) were added dropwise, and TBDPSCl (4.6 g, 1.1 eq) was added. The reaction was complete after 8 hours of TLC monitoring. Pyridine (12 eq, 14.5 ml) was added to the reaction solution, followed by the dropwise addition of benzoyl chloride (6 eq, 10.5 ml). The reaction was continued at room temperature (25°C) and completed after 12 hours. The reaction was quenched with a small amount of methanol in an ice bath. The reaction solution was concentrated to dryness, extracted with petroleum ether, and washed with saturated NaHCO3 solution and saturated brine until neutral. The organic layer was dried over anhydrous sodium sulfate for at least 3 hours, filtered, and concentrated to dryness to obtain crude compound 5 (two-step yield: 86.1%). 1H NMR (CDCl3, 300MHz) δ0.89 (t, J = 6.9Hz, 3H), 1.09 (s, 9H), 1.27 (s, 22H), 1.41-1.60 (m, 2H), 2.17 (br s,2H),3.57(m,1H),3.65-3.71(m,2H),3.92(dd,J=5.7,10.8Hz,1H),4.04(dd,J=3.9,10.8Hz,1H),7.39-7.50(m,6H),7.69-7.72(m,4H); 13 C NMR (CDCl3, 75MHz) δ14.1,19.0,22.6,25.6,26.7,29.3,29.5,29.6,29.7,31. 6,31.9,63.4,64.2,72.3,74.0,127.8,129.9,132.45,132.53,135.5,135.6.

[0090] Example 3

[0091]

[0092] At 0°C, the crude compound 5 (14.0 g, 1 eq) prepared in Example 2 was dissolved in THF (300 ml, 20 V) and stirred in a fluorination flask. 70% HF.Pyridine (10.12 g, 20 eq) was added dropwise to the reaction mixture. TLC monitoring indicated that the reaction was complete after 12 hours. The reaction was quenched with saturated NaHCO₃ solution until the aqueous layer was neutral. The reaction mixture was extracted with appropriate amounts of EA, washed with saturated brine and water, and the organic layer was dried over anhydrous sodium sulfate for at least 3 hours, filtered, concentrated to dryness, and purified by column chromatography to obtain compound 1 in a 78% yield. The total yield over four steps was 61.15%. [α]D 23 +15.8°(c 1.14,CHC13)

[0093] NMR data of compound 1: 1H NMR (600MHz, CDCl3) δ8.04(d,J=7.1Hz,2H),8.00(d,J=9.4Hz,2H),7.62(t,J=7.4H z,1H),7.56(t,J=6.2Hz,1H),7.48(t,J=7.8Hz,2H),7.42(t,J=7.8Hz,2H),5.60–5. 51(m,2H),3.99(t,J=7.9Hz,1H),3.81(p,J=6.1Hz,2H),2.40(dd,J=7.6,5.1Hz,1H ),2.00–1.82(m,2H),1.50–1.32(m,2H),1.29–1.15(m,21H),0.88(t,J=7.1Hz,3H).

[0094] 13 C NMR (101MHz, CDCl3) δ165.62,165.32,133.24,132.83,129.47,129.28,129.24,128.66,128.19,128.03,72.8 3,72.46,62.65,61.69,31.47,29.29,29.23,29.21,29.19,29.14,29.05,28.96,28.90,25.04,22.24,13.67.

[0095] Comparative Example 1

[0096] (Adopting the method in Journal of Medical Chemistry (2007), 50, 3489-3496.)

[0097]

[0098] A mixed solution of sodium azide (2.5 g, 31.5 mmol, 10 eq) in dichloromethane and water (1:1, 10 ml) was cooled to 0°C, and trifluoromethanesulfonic anhydride (1.1 ml, 6.3 mmol) was added dropwise to the reaction solution. The reaction was complete after 3 hours, and the mixture was extracted with dichloromethane (4 ml). The organic layer was washed with saturated sodium carbonate solution.

[0099] At room temperature, compound 2 (1 g, 3.1 mmol, 1 eq), anhydrous potassium carbonate (2.18 g, 15.8 mmol, 5 eq) and copper sulfate (20 mg, 0.125 mmol, 0.05 eq) were dissolved in a mixed solution of methanol (4 ml) and water (3 ml), and the mixture was added to the dichloromethane solution of TfN3 prepared above. An appropriate amount of methanol was added to form a homogeneous solution, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to obtain compound 3 with a yield of 89%.

[0100] Comparative Example 2

[0101] (Adopting the method of Journal of Organic Chemistry, 2006, 71(22):8661-8664)

[0102]

[0103] To a mixed solution of compound 3 (1.25 g, 3.64 mmol, 1 eq) in dichloromethane (18 ml) and DMF (4 ml) was added triethylamine (1.3 ml, 9.1 mmol, 3 eq), DMAP (22 mg, 0.18 mmol, 0.05 eq), and TBDPSCl (1.1 ml, 4.4 mmol, 1.2 eq) at 0°C under N2 protection, and the mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography to obtain compound 5 (1.84 g, 87%).

[0104] Comparative Example 3

[0105] (Adopting the method of Bioconjugate Chemistry (2013), 24(4), 586-594)

[0106]

[0107] Compound 6 (32 mg, 0.075 mmol) was dissolved in a mixed solvent of MeOH / CH2Cl2 / H2O (4 ml, 2:1:1), and K2CO3 (79 mg, 0.74 mmol), CuSO4 (168 μg, 1.1 μmol), and 1H-imidazolesulfonyl azide hydrochloride (88 mg, 0.42 mmol) were added in sequence. The reaction was allowed to proceed overnight, and the mixture was extracted with ethyl acetate (3 × 15 ml). The mixture was washed with brine (60 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated. The product was purified by column chromatography (3% ethyl acetate in hexane) (yield: 77%).

Claims

1. A method for preparing a compound of Formula 1, comprising the following steps: in an organic solvent, subjecting a compound of Formula 5 to a deprotection reaction with a hydrogen fluoride pyridine solution as shown below to obtain Compound 1; in, C 13 H 27 is n-tridecyl; the temperature of the deprotection reaction is 0°C; The method for preparing the compound shown in Formula 1 further comprises the following steps: The method for preparing the compound shown in Formula 5 comprises the following steps: (1) In an organic solvent, in the presence of N2, in the presence of a base and a pyridine catalyst, TBDPSCl is reacted with an azide compound as shown in Formula 3 to perform a primary alcohol protection reaction to obtain a compound as shown in Formula 4; (2) In the reaction solution of step (1), in the presence of pyridine, a secondary alcohol protection reaction is carried out on benzoyl chloride and the compound shown in Formula 4 to obtain a compound shown in Formula 5; Wherein, the organic solvent in step (1) is ultra-dry dichloromethane; The base is imidazole; The pyridine catalyst is DMAP; The method for preparing the compound shown in Formula 5 further comprises the following steps: the method for preparing the azide compound shown in Formula 3 comprises the following steps: in an organic solvent, in the presence of an alkali metal carbonate and a copper salt, reacting an amine compound shown in Formula 2 with an azide reagent to obtain the azide compound shown in Formula 3; the azide reagent is 1H-imidazolesulfonyl azide or a salt thereof; 2. The method for preparing the compound of formula 1 according to claim 1, wherein: The preparation method meets one or more of the following conditions: (1) In the deprotection reaction, the organic solvent is an ether solvent; (2) The mass volume ratio of the compound represented by Formula 5 to the organic solvent is 0.045 g / mL to 0.05 g / mL; (3) In the deprotection reaction, the equivalent ratio of the hydrogen fluoride pyridine solution to the compound represented by Formula 5 is (10-30):1; and (4) The deprotection reaction is carried out in a fluorination bottle.

3. The method for preparing the compound of formula 1 according to claim 2, wherein: The preparation method meets one or more of the following conditions: (1) In the deprotection reaction, the ether solvent is tetrahydrofuran; (2) The mass volume ratio of the compound represented by Formula 5 to the organic solvent is 0.046 g / mL; (3) In the deprotection reaction, the hydrogen fluoride pyridine solution is a 70% hydrogen fluoride pyridine solution; and (4) In the deprotection reaction, the equivalent ratio of the hydrogen fluoride pyridine solution to the compound represented by Formula 5 is 20:

1.

4. The method for preparing the compound of formula 1 according to claim 1, wherein The method for preparing the compound shown in Formula 5 satisfies one or more of the following conditions: (1) The mass volume ratio of the azide compound represented by Formula 3 to the organic solvent is 0.04 g / mL to 0.06 g / mL; (2) The equivalent ratio of the base to the azide compound shown in Formula 3 is (2.5-3):1; (3) The equivalent ratio of the pyridine catalyst to the azide compound shown in Formula 3 is (0-0.2):1; (4) The equivalent ratio of the TBDPSCl to the azide compound shown in Formula 3 is (1.0-1.2):1; (5) In the protection reaction of the primary alcohol, the reaction temperature is room temperature; (6) The equivalent ratio of the pyridine to the azide compound shown in Formula 3 is 12:1; (7) the equivalent ratio of the benzoyl chloride to the azide compound shown in Formula 3 is 6:1; (8) The protection reaction temperature of the secondary alcohol is room temperature 25°C; and (9) The post-processing operations of the preparation method are as follows: quenching, concentration, extraction, water washing, drying, and re-concentration.

5. The method for preparing the compound of formula 1 according to claim 4, wherein: The method for preparing the compound shown in Formula 5 satisfies one or more of the following conditions: (1) The mass volume ratio of the azide compound represented by Formula 3 to the organic solvent is 0.052 g / mL; (2) the equivalent ratio of the base to the azide compound shown in Formula 3 is 3:1; (3) the equivalent ratio of the pyridine catalyst to the azide compound shown in Formula 3 is 0.1:1; and (4) The equivalent ratio of the TBDPSCl to the azide compound shown in Formula 3 is 1.1:

1.

6. The method for preparing the compound of formula 1 according to claim 1, wherein: The method for preparing the azide compound shown in Formula 3 satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent and / or an ether solvent; (2) The mass volume ratio of the amine compound represented by Formula 2 to the organic solvent is 0.04 g / mL-0.06 g / mL; (3) The alkali metal carbonate is potassium carbonate; (4) The molar ratio of the alkali metal carbonate to the amine compound shown in Formula 2 is (1-2):1; (5) The copper salt is copper sulfate pentahydrate; (6) The molar ratio of the copper salt to the amine compound shown in Formula 2 is (0-1):1; (7) The salt of 1H-imidazolesulfonyl azide is 1H-imidazolesulfonyl azide hydrochloride; (8) The molar ratio of the azide reagent to the amine compound shown in Formula 2 is (1-2):1; (9) The temperature of the azide reaction is room temperature; (10) The reaction time of the azide reaction is 1-10 hours; and (11) The azide reaction also includes the following post-treatment: after the azide reaction is completed, the reaction solution is filtered, the filtrate is concentrated, slurried, filtered, dissolved, recrystallized and then filtered, and the filter cake is dried to obtain the azide compound shown in Formula 3.

7. The method for preparing the compound of formula 1 according to claim 6, wherein: The method for preparing the azide compound shown in Formula 3 satisfies one or more of the following conditions: (1) The alcohol solvent is methanol; (2) The ether solvent is tetrahydrofuran; (3) The organic solvent is an alcohol solvent and an ether solvent, and the volume ratio of the alcohol solvent to the ether solvent is 1:3; (4) The mass volume ratio of the amine compound represented by Formula 2 to the organic solvent is 0.049 g / mL; (5) The molar ratio of the alkali metal carbonate to the amine compound represented by Formula 2 is 1.5:1; (6) The molar ratio of the copper salt to the amine compound represented by Formula 2 is 0.01:1; (7) The molar ratio of the azide reagent to the amine compound shown in Formula 2 is 1.1:1; and (8) The reaction time is 4-5 hours.

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