A process for the preparation of (3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride

Abstract

The application provides a synthesis method of (3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (compound I), and a synthesis route of the compound I is as follows: wherein 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 provides an efficient synthesis method for the compound.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, 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

[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]dec-4-amine (TNO155) was first disclosed in the compound patent application WO2015107495A1, which is a small molecule protein tyrosine phosphatase-2 (SHP2) inhibitor, and shows good tolerability and disease control effect in patients with advanced solid tumors when combined with other inhibitors. The chiral amine fragment (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (compound II) is a key intermediate in the synthesis of the compound, which can increase cell penetration and lipophilicity, while the diastereoisomer (3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (compound I) is one of the important control samples required for quality control of compound II.

[0003]

[0004] There is only one method reported in the literature for the synthesis of the diastereoisomer (3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (compound I). 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 subjected to reduction and deprotection to generate compound 22; compound 22 is subjected to Mitsunobu reaction to generate compound 23; compound 23 is subjected to oxidation with Dess-Martin reagent to generate compound 24; compound 24 is subjected to reaction with iodomethane under basic conditions to generate compound 25; compound 25 is subjected to reaction with R-(+)-tert-butylsulfinamide to generate compound 26; compound 26 is subjected to chiral resolution with SFC to generate compound 27; and compound 27 is subjected to reaction under acidic conditions to generate compound I.

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

[0006]

[0007] The method is prepared through eight steps of addition under alkaline condition, ester bond reduction to alcohol, deprotection, intramolecular ring closure by Mitsunobu reaction, oxidation and alkyl substitution, the route is long, SFC is used for chiral resolution, the cost is high, the preparation period is long, and it is not conducive to rapid acquisition. SUMMARY

[0008] In view of the problems of multiple synthesis steps, high cost, and low yield caused by chiral resolution and other steps in the synthesis of (3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride in the prior art, the present application provides a synthesis method of diastereoisomer (3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride, an intermediate of a protein tyrosine phosphatase-2 (SHP2) inhibitor. The reaction product of the method has a single configuration, avoiding the chiral resolution step in the prior art, so that the synthesis operation is simple and the yield is high.

[0009] The present application first 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:

[0010]

[0011] X is halogen.

[0012] The present application also provides a synthesis method of compound 1, and the synthesis route is as follows:

[0013]

[0014] X is halogen.

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

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

[0017] Advantages of the present application:

[0018] The chemical synthesis method of the present application synthesizes isomer compound I with a single configuration through four steps, the route is shorter, chiral resolution is avoided, the yield is improved, and the synthesis cost is reduced. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Single crystal structure diagram of compound 5 in Example 3 DETAILED DESCRIPTION

[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, this applies throughout the specification and claims.

[0021] In this invention, the terms "comprising," "containing," "including," "comprising," "having," "containing," "characterized as," or any other variation thereof are intended to cover non-exclusive inclusion, conditional upon any expressly specified limitation. For example, a composition, mixture, process, or method comprising a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed, or elements inherent to such compositions, mixtures, processes, or methods.

[0022] In this invention, "composed of..." excludes any unspecified elements, steps, or ingredients. If in a claim, such a phrase makes the claim closed, excluding materials other than those described, except for conventional impurities associated with them. When the phrase "composed of..." appears in a clause of the body of a claim, rather than immediately following it, it limits only the elements mentioned in that clause; other elements are not excluded from the claim as a whole.

[0023] In this invention, "consistently composed of..." is used to define compositions or methods that include, in addition to those literally disclosed, materials, steps, features, components, or elements, provided that such additional materials, steps, features, components, or elements do not materially affect the essential and novel features of the subject matter. The term "consistently composed of..." falls between "comprising" and "composed of...".

[0024] The drying solvent of this invention refers to a solvent that has undergone drying treatment, in which the water content is extremely low, close to being water-free.

[0025] As used in this disclosure, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. When the number of carbon atoms is not used when describing "alkyl," it means that the alkyl group has any number of carbon atoms. When the number of carbon atoms is used when describing "alkyl," it means that the alkyl group has the stated number of carbon atoms. For example, an alkyl group can be C1-C1. 20alkyl, which means a saturated straight-chain or branched-chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can optionally be substituted with one or more substituents described in the present disclosure. Unless otherwise specified in detail, an alkyl group contains 1 to 20 carbon atoms. In some embodiments, an alkyl group contains 1 to 10 carbon atoms, such as "Ci-Cio alkyl"; in other embodiments, an alkyl group is an alkyl group containing 1 to 6 (1, 2, 3, 4, 5, or 6) carbon atoms, i.e., "Ci-C6alkyl"; in yet other embodiments, an alkyl group is an alkyl group containing 1 to 4 (1, 2, 3, or 4) carbon atoms, i.e., "Ci-C4alkyl"; in still other embodiments, an alkyl group contains 1 to 3 carbon atoms, i.e., "Ci-C3alkyl". 10 In some embodiments, an alkyl group contains 1 to 10 carbon atoms, such as "Ci-Cio alkyl"; in other embodiments, an alkyl group is an alkyl group containing 1 to 6 (1, 2, 3, 4, 5, or 6) carbon atoms, i.e., "Ci-C6alkyl"; in yet other embodiments, an alkyl group is an alkyl group containing 1 to 4 (1, 2, 3, or 4) carbon atoms, i.e., "Ci-C4alkyl"; in still other embodiments, an alkyl group contains 1 to 3 carbon atoms, i.e., "Ci-C3alkyl".

[0026] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), i-propyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), i-butyl (i-Bu, -CH2CH(CH3)2), s-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -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-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-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 (CI), bromine (Br) or iodine (I).

[0028] The present application provides a synthetic method of (3R,4S)-3-methyl-2-oxa-8- azaspiro[4.5]decane-4-amine hydrochloride (Compound I), the synthetic route of which is as follows:

[0029]

[0030] wherein X is halogen.

[0031] In the above synthetic method, the chiral carbon configuration connected with X in the compound 1 can be R type, S type or racemate.

[0032] Preferably, in the above synthetic method, in step (1), compound 1 is reacted with compound 2 in the presence of base A to prepare compound 3, and the base A is one or more of potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, preferably lithium diisopropylamide, and particularly preferably lithium diisopropylamide is prepared on site by reacting diisopropylamine with n-butyllithium. Preferably, compound 1 is reacted with compound 2 in the presence of base A in a solvent to prepare compound 3, and 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 inert gas protection, and the inert gas is preferably argon.

[0033] Preferably, in the above synthetic method, in step (2), compound 3 is reduced in the presence of a reducing agent to prepare compound 4, and the reducing agent is one of diisobutylaluminum hydride, lithium tetrahydroaluminate, lithium borohydride, sodium borohydride or potassium borohydride, preferably lithium tetrahydroaluminate. 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 synthetic method, in step (3), compound 4 is subjected to ring-closing reaction in the presence of 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 is subjected to ring-closing reaction in the presence of 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 step (4) of the above synthesis method, compound 5 is reacted in the presence of an acid to produce compound I, wherein the acid is hydrochloric acid, preferably hydrogen chloride gas, hydrogen chloride isopropyl alcohol solution, hydrogen chloride dioxane solution, hydrogen chloride ethyl acetate solution, and particularly preferably hydrogen chloride isopropyl alcohol solution. Preferably, compound 5 is reacted in the presence of an acid in a solvent to produce compound I, wherein the solvent is methanol, ethanol, isopropyl alcohol, dioxane, dichloromethane, ethyl acetate, isopropyl acetate or a mixture thereof, and preferably methanol.

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

[0037]

[0038] wherein,

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

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

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

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

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

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

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

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

[0047] Selectivity = Actual moles of target product / Theoretical moles of target product x 100%

[0048] Yield = Actual mass of target product / Theoretical mass of target product x 100%

[0049] In the following examples, the post-treatment of the reaction includes at least one of the following: cooling, filtering, rinsing, drying, reducing pressure, distilling, adjusting pH, extracting, concentrating, quenching, standing, crystallization, and recycling.

[0050] Unless otherwise specified, the raw materials used are 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 (7 g, 51 mmol, 1.0 eq) was added dropwise to dry DCM (70 ml), and diisobutylaluminum hydride (60 ml, 60 mmol, 1.2 eq, 1 mol / L cyclohexane solution) was slowly added dropwise at -78°C, and the reaction was carried out at -78°C for 2 h. After the reaction was completed, 5 ml of methanol was added dropwise at -78°C to quench the reaction, and the temperature was slowly raised to 0°C. Then 1 M hydrochloric acid aqueous solution (50 ml) was added dropwise at 0°C, and stirred for 1 h. The organic phase was retained, and the aqueous phase was extracted with DCM three times. The organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain compound A1-2 crude product, which was directly used in the next step.

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

[0056] A dry two-neck flask was charged with DCM solution (50 ml), Ti(OEt)4 (30 ml), compound A1-2 crude product, (R)-tert-butylsulfmamide (9.68 g, 80 mmol, 2.0 eq), and the temperature was raised to 35°C. The reaction was carried out at 35°C for 12 h. Then 30 ml of water was added to quench the reaction, and the liquid phase was collected by filtration. The organic phase was retained, and the aqueous phase was extracted with DCM three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography 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, (S)-ethyl 2-chloropropionate (7 g, 51 mmol, 1.0 eq) was added dropwise to dry DCM (70 ml) and diisobutylaluminum hydride (60 ml, 60 mmol, 1.2 eq, 1 mol / L in cyclohexane) was added dropwise slowly at -78 °C for 2 h. After the reaction was completed, 5 ml of methanol was added dropwise at -78 °C to quench the reaction, and the temperature was slowly raised to 0 °C. Then 1 M aqueous hydrochloric acid solution (50 ml) was added dropwise at 0 °C, and stirred for 1 h. The organic phase was retained, and the aqueous phase was extracted with DCM three times. The organic phase was combined, washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain compound B1-2 crude product, which was directly used in the next step.

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

[0062] A dry two-necked flask was charged with DCM solution (50 ml), Ti(OEt)4 (30 ml), compound B1-2 crude product, (R)-tert-butylsulfmamide (9.7 g, 80 mmol, 2.0 eq), and the temperature was raised to 35 °C. The reaction was incubated for 12 h. Then 30 ml of water was added to quench the reaction, and the liquid phase was collected by filtration. The organic phase was retained, and the aqueous phase was extracted with DCM three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified 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-((1 S,2R)-1 -(((R)-tert-butylsulfinyl)amino)-2- chloropropyl)piperidine-1,4-dicarboxylate

[0066] Under argon protection, dry THF solution 20 ml was added diisopropylamine (2.02 g, 20 mmol, 2 eq), cooling to 0 ℃, temperature control below 0 ℃, dropwise addition of n-butyl lithium (2.5 M cyclohexane solution) 8 ml, after adding, warming to room temperature, incubation for 10 min. Cooling to below -80 ℃, temperature control below -80 ℃, dropwise addition of N-Boc-4-piperidine carboxylic acid ethyl ester (3.2 g, 12 mmol, 1.2 eq.), dropwise, incubation for 1 h. Temperature control below -80 ℃, continue to dropwise addition of compound A1 (1.95 g, 10 mmol, 1.0 eq.), dropwise, incubation for 20 min, TLC spot plate detection of raw materials reaction complete. Saturated ammonium chloride quenching reaction, DCM extraction 3 times, combined organic phase, saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration, column purification, 3.85 g compound A2, yield 85%.

[0067] Synthesis of 24-((1S,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)-4- (hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[0068] Under argon protection, dry round bottom flask was added dry THF solution 30 ml, compound A2 (3.8 g, 8.5 mmol, 1.0 eq.), cooling to 0 ℃, LiAlH4 (315 mg, 8.5 mmol, 1.0 eq.) was added in batches, reaction for 2 min. The reaction liquid was poured into ice water quenching, filtration, collection of liquid phase, DCM extraction three times, combined organic phase, saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration, column purification, 2.85 g compound A3, yield 82%.

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

[0070] Under argon protection, dry two-port bottle was added compound A3 (500 mg, 1.22 mmol, 1.0 eq.), sodium hydroxide (196 mg, 4.88 mmol, 4.0 eq.), toluene 10 ml, methanol 3 ml, after adding, warming to 90 ℃, incubation for 24 h, TLC spot plate detection of raw materials reaction complete. Add water quenching, DCM extraction 3 times, combined organic phase, saturated brine washing of organic phase, anhydrous sodium sulfate drying, vacuum concentration after column purification, 420 mg compound 5, yield 92%.

[0071] 1H-NMR (400 MHz, CDC13): δ 4.25 ~ 3.94 (m, 2H), 3.78 ~ 3.71 (m, 2H), 3.56 ~ 3.51 (m, 1H), 3.29 (d, J = 12.0 Hz, 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 = 4.0 Hz, 3H), 1.21 (s, 9H).

[0072] Single crystal culture:

[0073] Take 20 mg of compound 5, slowly evaporate with a mixture of petroleum ether and ethyl acetate solvent (PE:EA = 30:1) at 10°C to get crystals.

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

[0075] A dry round-bottom flask was added with compound 5 (400 mg, 1.14 mmol, 1.0 eq), 5 mL MeOH in turn, cooled to 0°C, and 2 mL of 4M hydrochloric acid isopropanol solution was added dropwise at 0°C, and then the temperature was raised to room temperature after dropping. The reaction was carried out for 4 hours. After the reaction was completed, the solution was concentrated under vacuum to be slightly dry, dissolved in 0.5 mL of methanol, quickly added with 20 mL of ethyl acetate to precipitate the solid, and then filtered and washed with ethyl acetate. After drying, 280 mg of compound I was obtained with a yield of 91%.

[0076] 1 H-NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1H), 9.03 (s, 1H), 8.75 (s, 3H), 3.93 (d, J = 12.0 Hz, 1H), 3.89 ~ 3.84 (m, 1H), 3.66 (d, J = 8.0 Hz, 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 = 4.0 Hz, 3H).

[0077] Synthesis of compound I in Example 4

[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, dry THF solution 20 ml was added diisopropylamine (2.02 g, 20 mmol, 2 eq), cooling to 0 ℃, temperature control below 0 ℃, dropwise addition of n-butyllithium (2.5 M cyclohexane solution) 8 ml, after adding, warming to room temperature, incubation reaction for 10 min. Cooling to below -80 ℃, temperature control below -80 ℃, dropwise addition of N-Boc-4-piperidine carboxylic acid ethyl ester (3.2 g, 12 mmol, 1.2 eq), after dropping, incubation reaction for 1 h. Temperature control below -80 ℃, continue to dropwise addition of compound B1 (2 g, 10 mmol, 1.0 eq), after dropping, incubation reaction for 20 min, TLC spot plate detection of raw materials reaction complete. Saturated ammonium chloride quenching reaction, DCM extraction 3 times, combined organic phase, saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration, column purification, 4 g of compound B2 was obtained with a yield of 88%.

[0081] Step 24 - ((1S,2S)-1-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)-4- (hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester synthesis

[0082] Under argon, dry THF solution 20 ml was added diisopropylamine (2.02 g, 20 mmol, 2 eq), cooling to 0 ℃, temperature control below 0 ℃, dropwise addition of n-butyllithium (2.5 M cyclohexane solution) 8 ml, after adding, warming to room temperature, incubation reaction for 10 min. Cooling to below -80 ℃, temperature control below -80 ℃, dropwise addition of N-Boc-4-piperidine carboxylic acid ethyl ester (3.2 g, 12 mmol, 1.2 eq), after dropping, incubation reaction for 1 h. Temperature control below -80 ℃, continue to dropwise addition of compound B1 (2 g, 10 mmol, 1.0 eq), after dropping, incubation reaction for 20 min, TLC spot plate detection of raw materials reaction complete. Saturated ammonium chloride quenching reaction, DCM extraction 3 times, combined organic phase, saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration, column purification, 4 g of compound B2 was obtained with a yield of 88%.

[0083] Step 3 (3R,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester synthesis

[0084] Under argon, dry THF solution 20 ml was added diisopropylamine (2.02 g, 20 mmol, 2 eq), cooling to 0 ℃, temperature control below 0 ℃, dropwise addition of n-butyllithium (2.5 M cyclohexane solution) 8 ml, after adding, warming to room temperature, incubation reaction for 10 min. Cooling to below -80 ℃, temperature control below -80 ℃, dropwise addition of N-Boc-4-piperidine carboxylic acid ethyl ester (3.2 g, 12 mmol, 1.2 eq), after dropping, incubation reaction for 1 h. Temperature control below -80 ℃, continue to dropwise addition of compound B1 (2 g, 10 mmol, 1.0 eq), after dropping, incubation reaction for 20 min, TLC spot plate detection of raw materials reaction complete. Saturated ammonium chloride quenching reaction, DCM extraction 3 times, combined organic phase, saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration, column purification, 4 g of compound B2 was obtained with a yield of 88%.

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

[0086] Into a dry round bottom flask, compound 5 (400 mg, 1.14 mmol, 1.0 eq), 5 ml MeOH were added successively, cooled to 0 °C, 2 mL of 4M hydrochloric acid in isopropanol was added dropwise, after dropwise addition, the solution was allowed to warm to room temperature and react for 4 h. After the reaction was completed, the solution was concentrated under vacuum to dryness, 0.5 mL of methanol was added for dissolution, 20 mL of ethyl acetate was quickly added to precipitate the solid, suction filtration was performed, and the solid was washed with ethyl acetate, and dried to obtain 296 mg of compound I with a yield of 96%.

[0087] 1 H-NMR (400 MHz, DMSO-d6): δ 8.81 (brs, 5H), 3.94 (d, J = 8.0 Hz, 1H), 3.87-3.84 (m, 1H), 3.66 (d, J = 8.0 Hz, 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 = 4.0 Hz, 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] Into a dry round bottom flask, compound 5 (400 mg, 1.14 mmol, 1.0 eq), 5 ml MeOH were added successively, cooled to 0 °C, 2 mL of 4M hydrochloric acid in isopropanol was added dropwise, after dropwise addition, the solution was allowed to warm to room temperature and react for 4 h. After the reaction was completed, the solution was concentrated under vacuum to dryness, 0.5 mL of methanol was added for dissolution, 20 mL of ethyl acetate was quickly added to precipitate the solid, suction filtration was performed, and the solid was washed with ethyl acetate, and dried to obtain 296 mg of compound I with a yield of 96%.

[0092] Synthesis of step 24-((lS,2R)-l-(((R)-tert-butylsulfinyl)amino)-2-chloropropyl)-4- (hydroxymethyl)piperidine-l-carboxylic acid tert-butyl ester

[0093] Into a dry round bottom flask, dry THF 30 ml, compound A2 (100 mg, 0.22 mmol, 1.0 eq.), under argon protection, cool to 0 °C, add lithium borohydride (24 mg, 1.1 mmol, 5.0 eq.) portionwise, react at room temperature for 20 h. Quench with aqueous ammonium chloride solution, extract with DCM three times, combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuum, separate by preparative TLC plate to give 22 mg of compound A3, yield 24%.

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

[0095] Into a dry two-necked flask, add compound A3 (50 mg, 0.12 mmol, 1.0 eq.), potassium tert-butoxide (41 mg, 0.36 mmol, 3.0 eq.), tert-butanol 2 ml, successively, after addition, warm to 80 °C, keep the temperature for 24 h, TLC spot plate test shows that the starting material is completely reacted. Quench with water, extract with DCM three times, combine the organic phase, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, separate by preparative TLC plate to give 21 mg of compound 5, yield 45%.

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

[0097] Into a dry round bottom flask, add compound 5 (100 mg, 0.29 mmol, 1.0 eq.), 1 ml MeOH, cool to 0 °C, add 4M hydrogen chloride solution in dioxane 2 ml dropwise, after dropping, warm to room temperature, react for 4 h. After the reaction is complete, concentrate the solution in vacuum to be slightly dry, add 5 ml ethyl acetate to precipitate the solid, filter under suction, and wash with ethyl acetate, dry to give 57 mg of compound I, yield 87%.

[0098] Example 6-9 Synthesis of compound A3

[0099]

[0100] Example 6-8 The preparation is the same as example 3, only the type of reducing agent is changed, and the results are as follows:

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

[0102] Example No. Starting material Reducing agent Yield 6 A2 LiAlH4 82％ 7 A2 NaBH4 10％ 8 A2 Diisobutylaluminum hydride 35％

[0103] Example 9-13 Synthesis of compound 5

[0104]

[0105] Example 9-13 Synthesis of compound 5

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

[0107] Example No. Starting material Base Solvent Yield 9 A3 KOH Toluene + methanol 90％ 10 A3 Na2CO3 Toluene + methanol 17％ 11 A3 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] Example 14-15 Synthesis of compound I

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

[0112]

[0113] The above only describes the preferred embodiments of the present application, and it should be noted that, for those skilled in the art, without departing from the inventive concept, several modifications and improvements can be made, which are all within the scope of the present application.

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: Where X is a halogen.

2. The synthesis method according to claim 1, characterized in that, The chiral carbon connected to X in compound 1 can be in the form of R, S, or racemate.

3. The synthesis method as described in 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 bis(trimethylsilyl)aminopotassium, bis(trimethylsilyl)aminosodium, bis(trimethylsilyl)aminolithium, and diisopropylaminolithium.

4. The synthesis method as described in claim 3, characterized in that, In step (1), the base A is lithium diisopropylamino.

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

6. The synthesis method as described in claim 5, characterized in that, In step (2), the reducing agent is lithium aluminum hydride.

7. The synthesis method according to claim 1, characterized in that, In step (3), compound 4 is prepared by a cyclization reaction in the presence of base B to obtain compound 5, wherein 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.

8. The synthesis method according to claim 7, characterized in that, In step (3), the base B is either sodium hydroxide or potassium hydroxide.

9. 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, isopropanol hydrogen chloride solution, dioxane hydrogen chloride solution, or ethyl acetate hydrogen chloride solution.

10. The synthesis method according to claim 9, characterized in that, In step (4), the acid is a solution of isopropanol hydrochloride.

11. The synthesis method according to any one of claims 1-10, characterized in that, The synthetic route for compound 1 is as follows: in, X is a halogen; R stands for alkyl group.

12. The synthesis method according to claim 11, characterized in that, X is chlorine, bromine, or iodine; R is a C1-C6 alkyl group.

13. The synthesis method according to claim 12, characterized in that, R is methyl or ethyl.

14. The synthesis method according to claim 11, characterized in that, In compound 1-1, the chiral carbon bonded to X is either R-type, S-type, or racemic.

15. The synthesis method according to claim 14, characterized in that, In step a, compound 1-1 is reduced in the presence of a reducing agent to obtain compound 1-2, wherein the reducing agent is diisobutylaluminum hydride or lithium tritert-butoxyaluminum hydride.

16. The synthesis method according to claim 15, characterized in that, In step b, compounds 1-2 are reacted with (R)-tert-butylthionamide in the presence of a titanate ester to prepare compound 1, wherein the titanate ester ester is tetraethyl titanate or tetraisopropyl titanate.

17. The synthesis method according to claim 16, characterized in that, The titanate is tetraethyl titanate.

Images