Preparation method of (3R, 4S)-3-methyl-2-oxa-8-azaspiro [4.5] decane-4-amine hydrochloride

Abstract

The invention provides a synthesis method of (3R, 4S)-3-methyl-2-oxa-8-azaspiro [4.5] decane-4-amine hydrochloride (compound I), and the synthesis route is as follows: # imgabs0 #, and X is halogen. The preparation method has the advantages of short synthesis steps, single reaction product configuration, avoidance of chiral resolution in post-treatment and high yield, and an efficient synthesis method is provided for synthesis of the compound.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for synthesizing a diastereoisomer of a protein tyrosine phosphatase-2 (SHP2) inhibitor intermediate, (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride. Background Art

[0002] The compound (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (TNO155) was first disclosed in the compound patent application WO2015107495A1. It is a small molecule protein tyrosine phosphatase-2 (SHP2) inhibitor. When used in combination with other inhibitors, it shows good tolerability and disease control effects in patients with advanced solid tumors. Among them, the chiral amine fragment (3S, 4S)-3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine hydrochloride (Compound II) is a key intermediate in the synthesis of the compound, which can increase cell permeability and lipophilicity, while the non-enantiomer (3R, 4S)-3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine hydrochloride (Compound I) is one of the important reference substances required for quality control of Compound II.

[0003]

[0004] Regarding the synthesis method of the diastereoisomer (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (Compound I), there is currently one method reported in the literature. The reaction process of the synthesis method disclosed in WO2015107495A1 is summarized as follows: Compound 20 reacts with Compound 2 to generate Compound 21; Compound 21 is reduced and deprotected to generate Compound 22; Compound 22 is cyclized by Mitsunobu reaction to generate Compound 23; Compound 23 is oxidized by Dess-Martin reagent to generate Compound 24; Compound 24 reacts with iodomethane under alkaline conditions to generate Compound 25; Compound 25 reacts with R-(+)-tert-butylsulfenamide to generate Compound 26; Compound 26 is chirally resolved by SFC to obtain Compound 27; Compound 27 is reacted under acidic conditions to generate Compound I.

[0005] The synthetic route of the above method is as follows:

[0006]

[0007] This method is prepared through eight steps of reaction, including addition under alkaline conditions, ester bond reduction to alcohol, deprotection, Mitsunobu reaction intramolecular ring closure, oxidation, and alkyl substitution. The route is long and SFC is used for chiral separation, which is costly and has a long preparation cycle, making it difficult to obtain quickly. Summary of the invention

[0008] The invention aims at the problems that the synthesis of (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride in the prior art has many steps, high cost, and particularly requires steps such as chiral resolution, resulting in low yield. The invention provides a method for synthesizing the diastereoisomer (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride of a protein tyrosine phosphatase-2 (SHP2) inhibitor intermediate. The reaction product of the method has a single configuration, avoids the chiral resolution step in the prior art, and makes the synthesis operation simple and the yield high.

[0009] The present invention first provides a method for synthesizing (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (Compound I), and the synthetic route thereof is as follows:

[0010]

[0011] Wherein, X is a halogen.

[0012] The present invention also provides a method for synthesizing compound 1, and its synthetic route is as follows:

[0013]

[0014] in,

[0015] X is halogen, preferably chlorine, bromine or iodine;

[0016] R is an alkyl group, preferably a C1-C6 alkyl group, more preferably a methyl group or an ethyl group.

[0017] Beneficial effects of the present invention:

[0018] The chemical synthesis method of the present invention synthesizes a single-configuration isomer compound I through four-step reactions, has a short route, avoids chiral separation, improves the yield, and reduces the synthesis cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The single crystal structure of compound 5 in Example 3 DETAILED DESCRIPTION

[0020] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise explicitly stated, in the entire specification and claims.

[0021] As used herein, the terms "comprising," "including," "comprising," "including," "having," "containing," "containing," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any expressly specified limitation. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0022] The phrase "consisting of" in this invention excludes any unrecited element, step, or ingredient. If in a claim, such a phrase will render the claim closed-ended so that it does not include materials other than those recited, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause in the body of a claim, rather than immediately preceding it, it is limited only to the elements mentioned in that clause; other elements are not excluded from the claim as a whole.

[0023] In the present invention, "essentially consisting of..." is used to define a composition or method that includes materials, steps, features, components, or elements other than those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the subject matter. The term "essentially consisting of..." is intermediate between "comprising" and "consisting of..."

[0024] The dry solvent of the present invention refers to a solvent that has been dried and has an extremely low water content, close to being free of water.

[0025] The term "alkyl" as used in the present disclosure means a saturated straight or branched monovalent hydrocarbon group. When the number of carbon atoms is not used when describing an "alkyl", it means that the alkyl has any number of carbon atoms. When the number of carbon atoms is used when describing an "alkyl", it means that the alkyl has the stated number of carbon atoms. For example, an alkyl group can be C1-C 20Alkyl refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described in the present disclosure. Unless otherwise specified, the alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, such as "C1-C 10 In some other embodiments, the alkyl group is an alkyl group containing 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms, i.e., a "C1-C6 alkyl"; in some other embodiments, the alkyl group is an alkyl group containing 1-4 (1, 2, 3 or 4) carbon atoms, i.e., a "C1-C4 alkyl"; in some other embodiments, the alkyl group contains 1-3 carbon atoms, i.e., a "C1-C3 alkyl".

[0026] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), u, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0027] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0028] The present invention first provides a method for synthesizing (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (Compound I), and the synthetic route thereof is as follows:

[0029]

[0030] Wherein, X is a halogen.

[0031] In the above synthesis method, the chiral carbon configuration connected to X in the compound 1 can be R-type, S-type or racemic.

[0032] Preferably, in the above synthesis method, in step (1), compound 1 reacts with compound 2 in the presence of base A to prepare compound 3, wherein base A is one or more of potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide, preferably lithium diisopropylamide, and particularly preferably lithium diisopropylamide prepared in situ by reacting diisopropylamine with n-butyllithium. Preferably, compound 1 reacts with compound 2 in the presence of base A in a solvent to prepare compound 3, wherein the solvent is tetrahydrofuran, n-hexane, n-heptane, benzene, toluene, ethylbenzene or a mixed solvent thereof, preferably tetrahydrofuran. Preferably, the reaction is carried out under the protection of an inert gas, wherein the inert gas is preferably argon.

[0033] Preferably, in the above synthesis method, in step (2), the compound 3 is subjected to a reduction reaction in the presence of a reducing agent to prepare compound 4, and the reducing agent is one of diisobutylaluminum hydride, lithium aluminum tetrahydride, lithium borohydride, sodium borohydride or potassium borohydride, preferably lithium aluminum tetrahydride. Preferably, the reduction reaction of step (2) is carried out in a solvent, and the solvent is a dry solvent, preferably dry tetrahydrofuran or 2-methyltetrahydrofuran.

[0034] Preferably, in the above synthesis method, in step (3), compound 4 undergoes a ring-closure reaction in the presence of a base B to prepare compound 5, and the base B is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide, preferably sodium hydroxide and potassium hydroxide. Preferably, compound 4 undergoes a ring-closure reaction in the presence of a base B in a solvent to prepare compound 5, and the solvent is toluene, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a mixed solvent thereof, preferably a mixed solvent of toluene and methanol.

[0035] Preferably, in the above synthesis method, in step (4), compound 5 is reacted in the presence of an acid to prepare compound I, and the acid is hydrochloric acid, preferably hydrogen chloride gas, hydrogen chloride isopropanol solution, hydrogen chloride dioxane solution, hydrogen chloride ethyl acetate solution, and hydrogen chloride isopropanol solution is particularly preferred. Preferably, compound 5 is reacted in the presence of an acid in a solvent to prepare compound I, and the solvent is methanol, ethanol, isopropanol, dioxane, dichloromethane, ethyl acetate, isopropyl acetate or a mixed solvent thereof, preferably methanol.

[0036] In the above synthesis method, the synthesis route of compound 1 is as follows:

[0037]

[0038] in,

[0039] X is halogen, preferably chlorine, bromine or iodine;

[0040] R is an alkyl group, preferably a C1-C6 alkyl group, more preferably a methyl group or an ethyl group.

[0041] Preferably, in the synthesis route of the above compound 1, the chiral carbon connected to X in compound 1-1 is R-type, S-type or racemic.

[0042] Preferably, in the synthetic route of the above-mentioned compound 1, the compound 1-1 in step a is subjected to a reduction reaction in the presence of a reducing agent to obtain compound 1-2, and the reducing agent is diisobutylaluminum hydride or lithium tri-tert-butoxyaluminum hydride. Preferably, the reaction temperature of the reduction reaction is -100--50°C, preferably -90--60°C, most preferably -78°C, and the reaction time is 1-5h, preferably 2-4h.

[0043] Preferably, in the synthetic route of the above compound 1, in step b, compound 1-2 is reacted with (R)-tert-butylsulfinamide in the presence of a titanate to prepare compound 1, wherein the titanate is tetraethyl titanate or tetraisopropyl titanate, more preferably tetraethyl titanate. The reaction temperature is room temperature to 50°C, preferably 35°C, and the reaction time is 5-15h, preferably 10-15h.

[0044] The present invention is further described with the following examples, but the protection scope of the present invention is not limited to the examples. The contents of reactants and products were measured by liquid chromatography (Agilent HPLC 1260).

[0045] The conversion and selectivity of the reaction were calculated by the following formula:

[0046] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0047] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%

[0048] Yield = actual mass of target product / theoretical mass of target product × 100%

[0049] In the following embodiments, the post-treatment of the reaction includes at least one of cooling, filtering, rinsing, drying, reducing pressure, distilling, adjusting pH, extracting, concentrating, quenching, standing, crystallizing, removing impurities and recycling;

[0050] Unless otherwise specified, all raw materials used were commercially available products.

[0051] Example 1 Synthesis of Compound A1

[0052]

[0053] Step 1 Synthesis of (R)-2-chloropropanal

[0054] Under argon protection, (R)-ethyl 2-chloropropionate (7g, 51mmol, 1.0eq) was added dropwise to dry DCM (70ml), and diisobutylaluminum hydride (60ml, 60mmol, 1.2eq, 1mol / L cyclohexane solution) was slowly added dropwise at -78°C, and the mixture was reacted at -78°C for 2h. After the reaction was completed, 5ml of methanol was added dropwise at -78°C to quench the reaction, and the temperature was slowly raised to 0°C. 50ml of 1M hydrochloric acid aqueous solution was added dropwise at 0°C, and stirred for 1h. The liquid was separated, and the organic phase was retained. The aqueous phase was extracted with DCM for 3 times, and the organic phases were combined. The organic phases were washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude compound A1-2, which was directly used in the next step.

[0055] Step 2 (R)-N-((R,E)-2-chloropropylidene)-2-methylpropane-2-sulfenamide

[0056] Add 50 ml of DCM solution, 430 ml of Ti(OEt), crude compound A1-2, (R)-tert-butylsulfinamide (9.68 g, 80 mmol, 2.0 eq) to a dry two-necked flask, heat to 35°C, and keep warm for 12 h. Add 30 ml of water to the reaction system for quenching, filter, collect the liquid phase, separate, retain the organic phase, extract the aqueous phase with DCM three times, combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuo, and purify by column to obtain 6.63 g of compound A1, with a two-step yield of 68%.

[0057] Example 2 Synthesis of Compound B1

[0058]

[0059] Step 1: Synthesis of (S)-2-chloropropanal

[0060] Under argon protection, (S)-2-chloropropionic acid ethyl ester (7g, 51mmol, 1.0eq) was added dropwise to dry DCM (70ml), and diisobutylaluminum hydride (60ml, 60mmol, 1.2eq, 1mol / L cyclohexane solution) was slowly added dropwise at -78°C, and the reaction was carried out at -78°C for 2h. After the reaction was completed, 5ml of methanol was added dropwise at -78°C to quench the reaction, and the temperature was slowly raised to 0°C. 50ml of 1M hydrochloric acid aqueous solution was added dropwise at 0°C, and stirred for 1h. The liquid was separated, and the organic phase was retained. The aqueous phase was extracted with DCM for 3 times, and the organic phases were combined, and the organic phases were washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude compound B1-2, which was directly used in the next step.

[0061] Step 2 (R)-N-((S,E)-2-chloropropylidene)-2-methylpropane-2-sulfenamide

[0062] Add 50 ml of DCM solution, 430 ml of Ti(OEt), crude compound B1-2, (R)-tert-butylsulfinamide (9.7 g, 80 mmol, 2.0 eq) to a dry two-necked flask, heat to 35°C, and keep warm for 12 h. Add 30 ml of water to the reaction system for quenching, filter, collect the liquid phase, separate, retain the organic phase, extract the aqueous phase with DCM three times, combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuo, and purify by column to obtain 6.75 g of compound B1, with a two-step yield of 69%.

[0063] Example 3 Synthesis of Compound I

[0064]

[0065] Step 11-(tert-Butyl)4-ethyl 4-((1S,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)piperidine-1,4-dicarboxylate

[0066] Under argon protection, add diisopropylamine (2.02g, 20mmol, 2eq) to 20ml of dry THF solution, cool to 0℃, control the temperature below 0℃, add 8ml of n-butyl lithium (2.5M cyclohexane solution), add, warm to room temperature, and keep warm for 10min. Cool to below -80℃, control the temperature below -80℃, add N-Boc-4-piperidinic acid ethyl ester (3.2g, 12mmol, 1.2eq), add dropwise, keep warm for 1h. Control the temperature below -80℃ and continue to add compound A1 (1.95g, 10mmol, 1.0eq.), add dropwise, keep warm for 20min, and detect the complete reaction of raw materials by TLC spot plate. Quench the reaction with saturated ammonium chloride, extract 3 times with DCM, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by column to obtain 3.85g of compound A2 with a yield of 85%.

[0067] Step 2 Synthesis of tert-butyl 4-((1S,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

[0068] Under argon protection, add 30 ml of dry THF solution and compound A2 (3.8 g, 8.5 mmol, 1.0 eq) to a dry round-bottom flask, cool to 0°C, add LiAlH4 (315 mg, 8.5 mmol, 1.0 eq) in batches, and react for 2 min. Pour the reaction solution into ice water for quenching, filter, collect the liquid phase, extract with DCM three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by column to obtain 2.85 g of compound A3 with a yield of 82%.

[0069] Step 3 Synthesis of tert-butyl (3R, 4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0070] Under argon protection, compound A3 (500 mg, 1.22 mmol, 1.0 eq), sodium hydroxide (196 mg, 4.88 mmol, 4.0 eq), 10 ml toluene, and 3 ml methanol were added to a dry two-necked bottle in sequence. After addition, the temperature was raised to 90°C and kept for 24 hours. The reaction of the raw materials was complete when detected by TLC. Water was added to quench, and DCM was extracted 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column to obtain 420 mg of compound 5 with a yield of 92%.

[0071] 1H-NMR (400MHz, CDCl3): δ4.25~3.94(m,2H), 3.78~3.71(m,2H), 3.56~3.51(m,1H), 3.29(d,J=12.0Hz,1H), 2.96~2 .88(m,1H),2.65~2.58(m,2H),1.87(s,1H),1.57(s,1H),1.38~1.35(m,11H),1.30(d,J=4.0Hz,3H),1.21(s,9H).

[0072] Single crystal culture:

[0073] 20 mg of compound 5 was taken and slowly evaporated at 10° C. using a mixture of petroleum ether and ethyl acetate (PE:EA=30:1) to obtain crystals.

[0074] Step 4 Synthesis of (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride

[0075] Compound 5 (400 mg, 1.14 mmol, 1.0 eq) and 5 ml MeOH were added to a dry round-bottom flask in sequence, and the temperature was lowered to 0°C. 2 ml of 4 M hydrochloric acid in isopropanol solution was added dropwise at 0°C. After the addition was completed, the temperature was raised to room temperature and the reaction was continued for 4 h. After the reaction was completed, the solution was concentrated to slightly dryness in vacuo, 0.5 ml of methanol was added to dissolve, 20 ml of ethyl acetate was quickly added to precipitate the solid, which was filtered and washed with ethyl acetate. After drying, 280 mg of compound I was obtained, with a yield of 91%.

[0076] 1 H-NMR (400MHz, DMSO-d6): δ9.26(s,1H),9.03(s,1H),8.75(s,3H),3.93(d,J=12.0Hz,1H),3.89~3.84(m,1H),3.66(d,J=8.0Hz,1H),3.29~3.24( m,1H),3.17~3.13(m,1H),3.03~2.93(m,2H),2.83~2.77(m,1H),1.97~1 .94(m,1H),1.83~1.74(m,2H),1.70~1.66(m,1H),1.33(d,J=4.0Hz,3H).

[0077] Example 4 Synthesis of Compound I

[0078]

[0079] Step 11-(tert-Butyl)4-ethyl 4-((1S,2S)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)piperidine-1,4-dicarboxylate

[0080] Under argon protection, add diisopropylamine (2.02g, 20mmol, 2eq) to 20ml of dry THF solution, cool to 0℃, control the temperature below 0℃, add 8ml of n-butyl lithium (2.5M cyclohexane solution), warm to room temperature, and keep warm for 10min. Cool to below -80℃, control the temperature below -80℃, add N-Boc-4-piperidinic acid ethyl ester (3.2g, 12mmol, 1.2eq), and keep warm for 1h. Control the temperature below -80℃ and continue to add compound B1 (2g, 10mmol, 1.0eq), and keep warm for 20min. TLC spot plate detection shows that the raw material reaction is complete. Quench the reaction with saturated ammonium chloride, extract with DCM 3 times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by column to obtain 4g of compound B2 with a yield of 88%.

[0081] Step 2 Synthesis of tert-butyl 4-((1S,2S)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

[0082] Under argon protection, add 30 ml of dry THF solution and compound B2 (4 g, 8.8 mmol, 1.0 eq.) to a dry round-bottom flask, cool to 0°C, add LiAlH4 (320 mg, 8.8 mmol, 1.0 eq.) in batches, and react for 2 min. Pour the reaction solution into ice water for quenching, filter, collect the liquid phase, extract with DCM three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify by column to obtain 2.9 g of compound B3 with a yield of 82%.

[0083] Step 3 Synthesis of tert-butyl (3R, 4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0084] Under argon protection, compound B3 (500 mg, 1.22 mmol, 1.0 eq), sodium hydroxide (200 mg, 4.88 mmol, 4.0 eq), 10 ml toluene, and 3 ml methanol were added to a dry two-necked bottle in sequence. After addition, the temperature was raised to 90°C and kept for 24 hours. The reaction of the raw materials was complete when detected by TLC spot plate. Water was added to quench, and DCM was extracted 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column to obtain 430 mg of compound 5 with a yield of 94%.

[0085] Step 4 Synthesis of (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride

[0086] Compound 5 (400 mg, 1.14 mmol, 1.0 eq) and 5 ml MeOH were added to a dry round-bottom flask in sequence, and the temperature was lowered to 0°C. 2 ml of 4 M hydrochloric acid in isopropanol solution was added dropwise at 0°C. After the addition was completed, the temperature was raised to room temperature and the reaction was continued for 4 h. After the reaction was completed, the solution was concentrated to slightly dryness in vacuo, 0.5 ml of methanol was added to dissolve it, 20 ml of ethyl acetate was quickly added to precipitate the solid, which was filtered and washed with ethyl acetate. After drying, 296 mg of compound I was obtained, with a yield of 96%.

[0087] 1 H-NMR (400MHz, DMSO-d6): δ8.81(brs,5H),3.94(d,J=8.0Hz,1H),3.87~3.84(m,1H),3.66(d,J=8.0Hz,1H),3.29~3.26(m,1H),3.17 ~3.14(m,1H),3.04~2.95(m,2H),2.84~2.78(m,1H),1.99~1.96(m,1H),1.82~1.75(m,2H),1.71~1.64(m,1H),1.33(d,J=4.0Hz,3H).

[0088] Example 5 Synthesis of Compound I

[0089]

[0090] Step 11-(tert-Butyl)4-ethyl 4-((1S,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)piperidine-1,4-dicarboxylate

[0091] Under argon protection, add LiHMDS (1mL, 1.02mmol, 2.0eq) to 10ml of dry THF solution. Cool down to below -78℃, control the temperature below -78℃, add N-Boc-4-piperidinic acid ethyl ester (160mg, 0.61mmol, 1.2eq) dropwise, and keep warm for 1h. Control the temperature below -80℃ and continue to add compound A1 (100mg, 0.51mmol, 1.0eq) dropwise, and keep warm for 20min. TLC spot plate detection shows that the raw material has reacted completely. Quench the reaction with saturated ammonium chloride, extract with DCM 3 times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and separate on a preparative thin layer chromatography plate to obtain 101mg of compound A2 with a yield of 43%.

[0092] Step 2 Synthesis of tert-butyl 4-((1S,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

[0093] Under argon protection, add 30 ml of dry THF and compound A2 (100 mg, 0.22 mmol, 1.0 eq.) to a dry round-bottom flask, cool to 0°C, add lithium borohydride (24 mg, 1.1 mmol, 5.0 eq.) in batches, and react at room temperature for 20 h. Quench with aqueous ammonium chloride solution, extract with DCM three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and separate on a preparative thin layer chromatography plate to obtain 22 mg of compound A3, with a yield of 24%.

[0094] Step 3 Synthesis of tert-butyl (3R, 4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0095] Under argon protection, compound A3 (50 mg, 0.12 mmol, 1.0 eq), potassium tert-butoxide (41 mg, 0.36 mmol, 3.0 eq), and 2 ml of tert-butanol were added to a dry two-necked bottle in sequence. After addition, the temperature was raised to 80°C and kept for 24 hours. The reaction of the raw materials was complete when detected by TLC. Water was added to quench the mixture, and DCM was extracted three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by preparative thin layer chromatography to obtain 21 mg of compound 5 with a yield of 45%.

[0096] Step 4 Synthesis of (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride

[0097] Compound 5 (100 mg, 0.29 mmol, 1.0 eq) and 1 ml of MeOH were added to a dry round-bottom flask in sequence, and the temperature was lowered to 0°C. 2 ml of 4 M hydrogen chloride dioxane solution was added dropwise at 0°C. After the addition was completed, the temperature was raised to room temperature and the reaction was continued for 4 hours. After the reaction was completed, the solution was concentrated to slightly dryness in vacuo, 5 ml of ethyl acetate was added to precipitate the solid, which was filtered and washed with ethyl acetate. After drying, 57 mg of compound I was obtained, with a yield of 87%.

[0098] Example 6-9 Synthesis of Compound A3

[0099]

[0100] The specific preparation operations of Examples 6-8 were the same as those of Example 3, except that the type of reducing agent was changed. The results were as follows:

[0101] Table 1 Effect of reducing agent in the synthesis of compound A3

[0102] Example No. raw material reducing agent Yield 6 A2 <![CDATA[LiAlH4]]> 82％ 7 A2 <![CDATA[NaBH4]]> 10％ 8 A2 Diisobutylaluminum hydride 35％

[0103] Example 9-13 Synthesis of Compound 5

[0104]

[0105] The specific operations of Examples 9-13 refer to Example 3, and the results of only changing the base in the reaction are as follows:

[0106] Table 2 Effect of base in the synthesis of compound 5

[0107] Example No. raw material Alkali Solvents Yield 9 A3 KOH Toluene + methanol 90％ 10 A3 <![CDATA[Na2CO3]]> Toluene + methanol 17％ 11 A3 <![CDATA[K2CO3]]> Toluene + methanol 15％ 12 A3 NaH Toluene 40％ 13 A3 t-BuOK t-BuOH 45％

[0108] Example 14-15 Synthesis of Compound I

[0109]

[0110] The specific operation of Example 14-15 was prepared by referring to Example 3, and the results of only changing the acid in the reaction were as follows:

[0111] Table 3 Effect of acid in the synthesis steps of compound I

[0112]

[0113] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing (3R, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (Compound I), characterized in that: Its synthetic route is as follows: Wherein, X is a halogen.

2. The synthesis method according to claim 1, characterized in that The chiral carbon configuration connected to X in the compound 1 can be R-type, S-type or racemic.

3. The synthesis method according to claim 1, characterized in that In step (1), compound 1 reacts with compound 2 in the presence of base A to prepare compound 3, wherein base A is one or more of potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide, preferably lithium diisopropylamide.

4. The synthesis method according to claim 1, characterized in that In step (2), compound 3 is subjected to a reduction reaction in the presence of a reducing agent to prepare compound 4, wherein the reducing agent is one of diisobutylaluminum hydride, lithium aluminum tetrahydride, lithium borohydride, sodium borohydride or potassium borohydride, preferably lithium aluminum tetrahydride.

5. The synthesis method according to claim 1, characterized in that In step (3), compound 4 undergoes a ring-closure reaction in the presence of a base B to prepare compound 5, wherein the base B is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide, preferably one of sodium hydroxide and potassium hydroxide.

6. The synthesis method according to claim 1, characterized in that In step (4), compound 5 is reacted in the presence of an acid to prepare compound I, wherein the acid is hydrogen chloride gas, hydrogen chloride isopropanol solution, hydrogen chloride dioxane solution, or hydrogen chloride ethyl acetate solution; hydrogen chloride isopropanol solution is particularly preferred.

7. The synthesis method according to any one of claims 1 to 6, characterized in that The synthetic route of compound 1 is as follows: in, X is halogen, preferably chlorine, bromine or iodine; R is an alkyl group, preferably a C1-C6 alkyl group, more preferably a methyl group or an ethyl group.

8. The synthesis method according to claim 7, characterized in that The chiral carbon connected to X in compound 1-1 is R-type, S-type or racemic.

9. The synthesis method according to claim 8, characterized in that Step a: Compound 1-1 is subjected to reduction reaction in the presence of a reducing agent to obtain compound 1-2, wherein the reducing agent is diisobutylaluminum hydride or lithium tri-tert-butoxyaluminum hydride.

10. The synthesis method according to claim 9, characterized in that In step b, compound 1-2 reacts with (R)-tert-butylsulfinamide in the presence of titanate to prepare compound 1, wherein the titanate is tetraethyl titanate or tetraisopropyl titanate, more preferably tetraethyl titanate.

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