Spiro compound and preparation method of intermediate thereof

Abstract

The invention relates to a preparation method of a spiro compound and an intermediate thereof. The preparation method comprises the step of reacting a compound shown in a formula (V) with a Grignard reagent to prepare the compound shown in the formula (IV). The method is high in yield, mild in reaction condition and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a method for preparing a spiro compound and an intermediate thereof. Background Art

[0002] COVID-19 caused by the infection of the novel coronavirus (SARS-CoV-2) is an acute respiratory infectious disease. SARS-CoV-2 has spread widely around the world. It has high infectivity and mortality, and has been listed as an international public health emergency of concern by the World Health Organization, posing a great threat to the lives and health of all mankind.

[0003] Currently, research on anti-SARS-CoV-2 drugs is actively underway both at home and abroad. An ideal anti-SARS-CoV-2 drug can selectively interfere with the replication cycle of the SARS-CoV-2 virus, thereby inhibiting its replication process. At the same time, it does not affect the normal physiological functions of host cells. Related popular targets include: RNA polymerase (RdRp), SARS-CoV S protein (spike protein), ACE2 (angiotensin-converting enzyme 2), 3CL protease (3CL pro , M pro ), papain-like protease (PL pro ), etc.

[0004] Among them, 3CL pro , also known as 3CL protease or main protease, is a cysteine protease and plays an important role in the virus replication process. The polyprotein precursor produced by the translation of viral RNA after entering the host cell is mainly cleaved by 3CL protease (3CL pro ) and papain-like protease (PL pro ) to form various functional proteins necessary for the virus, and these proteins will further participate in the virus RNA replication process. Therefore, inhibiting the activity of 3CL pro will prevent virus infection and replication. At the same time, 3CL pro has no homologous protein in the human body, which makes 3CL pro an ideal target for antiviral drug research and development. In addition, 3CL pro is highly conserved among all coronaviruses. Research shows that the 3CL protease of SARS-CoV-2 differs from that of SARS-CoV by only 12 amino acids, with a homology of up to 96%, and the substrate-binding pocket part is 100% conserved, which can avoid drug resistance caused by virus mutation. At the same time, the 3CL protease inhibitors screened have a certain degree of broad-spectrum anti-coronavirus ability and can be extended to the treatment of other types of coronavirus infections. Currently, multiple inhibitors targeting 3CL pro have been reported.

[0005] Recently, the world is in a high-risk period of the raging coronavirus, and with the emergence of various new mutant strains, the pressure to fight the coronavirus is huge. Therefore, it is of great significance to actively develop broad-spectrum 3CL protease inhibitors against SARS-CoV-2.

[0006] The currently disclosed patent applications for 3CL protease inhibitors include WO2021250648A1, WO2021226546A1, WO2021252644A1, WO2021212039A1, WO2021252491A1, WO2022020242A1, WO2022013684A1, WO2022208262A1, etc. Among them, multiple 3CL protease inhibitors share common intermediates. SUMMARY OF THE INVENTION

[0007] One aspect of the present disclosure provides a method for preparing a compound of formula (IV) or a salt thereof, comprising the step of reacting a compound of formula (V) with a Grignard reagent to prepare a compound of formula (IV), wherein,

[0008] R1 is selected from hydrogen, amino, and amino protected by an amino protecting group,

[0009] R2 is selected from hydrogen and a carboxyl protecting group,

[0010] R3 is C 1-6 alkyl,

[0011]

[0012] In some embodiments, the amino protecting group described in the present disclosure is selected from acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, formyl, benzoyl, phthaloyl, benzyl, trityl, 2,5-dimethylpyrrolyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl, such as tert-butoxycarbonyl.

[0013] In some embodiments, R1 is -NHBoc. In some embodiments, R1 is -N(Boc)2.

[0014] In some embodiments, the carboxyl protecting group described in the present disclosure is selected from methyl, ethyl, isopropyl, allyl, isopentenyl, and trimethylsilylethyl, such as methyl, ethyl, isopropyl.

[0015] In some embodiments, R3 is methyl, ethyl, or isopropyl.

[0016] In some embodiments, the Grignard reagent is selected from magnesium ethyl bromide and magnesium ethyl chloride. The molar ratio of the compound represented by formula (V) to the Grignard reagent is 1:1 - 1:10, such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

[0017] In some embodiments, the reaction is carried out in the presence of a catalyst, such as Ti(i-PrO)4, Ti(i-PrO)3Cl, Ti(t-BuO)3Cl or Ti(t-BuO)4. The molar ratio of the compound represented by formula (V) to the catalyst is 1:1 - 1:10, such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

[0018] In some embodiments, the reaction solvent is independently selected from one or more of ethyl acetate, isopropyl acetate, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropanol, propanol, ethanol, methanol, such as one or more of ether, tetrahydrofuran and toluene.

[0019] In some embodiments, the reaction temperature can be -70 to 30 °C, such as -60 °C, -50 °C, -40 °C, -30 °C, -20 °C, -10 °C, 0 °C, 10 °C, 20 °C.

[0020] In some embodiments, R1 is -N(Boc)2, and the method further includes the step of preparing the compound represented by formula (V) from the compound represented by formula (VI), wherein R1' is -NHBoc.

[0021]

[0022] The present disclosure also provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, including the method for preparing the compound represented by formula (IV) or a salt thereof as described in the present disclosure.

[0023]

[0024] In some embodiments, the compound represented by formula (IV) is the compound represented by formula (IV-1), and the method further includes the step of reacting the compound represented by formula (IV-1) with the compound represented by formula (III) and the compound represented by formula (II), wherein R is selected from hydrogen, methyl, ethyl and isopropyl.

[0025]

[0026] The compound represented by formula (II), the compound represented by formula (I), or a pharmaceutically acceptable salt thereof can be prepared by referring to the methods disclosed in patents or applications such as CN202311780153.8, which are incorporated herein by reference in their entirety.

[0027] In some embodiments, the preparation method of the present disclosure optionally further comprises a purification step, and the purification step comprises one or more of column chromatography, solvent trituration, and recrystallization.

[0028] The salts of the compounds described in the present disclosure can be inorganic acid salts and organic acid salts. The inorganic acid salts can be hydrochloride, sulfate, phosphate, hydrobromide, trifluoroacetate, etc., and the organic acids can be formate, acetate, sulfonate, optionally substituted alkyl sulfonate, succinate, maleate, tartrate, citrate, lactate, oxalate, gluconate, fumarate, malonate, malate, etc.

[0029] On the other hand, the present disclosure provides a compound represented by formula (V) or a salt thereof.

[0030]

[0031] Wherein, R1 is selected from hydrogen, amino, and amino protected by an amino protecting group.

[0032] R2 is selected from hydrogen and a carboxyl protecting group.

[0033] R3 is C 1-6 alkyl.

[0034] In some embodiments, R1 is -NHBoc. In some embodiments, R1 is -N(Boc)2.

[0035] In some embodiments, R3 is methyl, ethyl, or isopropyl.

[0036] The preparation methods of the spiro compounds and their intermediates described in the present disclosure have inexpensive and readily available starting materials, simple processes, high stereoselectivity, controllable isomers, can avoid SFC resolution, and directly obtain products with the target configuration, meeting the requirements of industrial scale-up.

[0037] In the preparation methods described in the present disclosure, the reactions connected by "→" all refer to one-step reactions to obtain the described products.

[0038] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0039] "Carboxyl protecting group" is a suitable group known in the art for protecting carboxyl groups. See the literature ("Protective Groups in Organic Synthesis", 5Th a carboxyl protecting group in (Ed.T.W.Greene & P.G.M.Wuts), 5Th Ed., and preferably, the carboxyl protecting group may be a substituted or unsubstituted C 1-10 straight-chain or branched alkyl group, a substituted or unsubstituted C 2-10 straight-chain or branched alkenyl or alkynyl group, a substituted or unsubstituted C 3-8 cyclic alkyl group, a substituted or unsubstituted C 5-10 aryl or heteroaryl group, or a (C 1-8 alkyl or aryl)3silyl group; preferably a C 1-6 straight-chain or branched alkyl group, more preferably a C 1-4 straight-chain or branched alkyl group. For example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

[0040] An "amino protecting group" is a group known in the art and capable of protecting an amino group. See the amino protecting groups in the literature ("Protective Groups in Organic Synthesis", 5Th Ed.T.W.Greene & P.G.M.Wuts). By way of example, and without limitation, carbamate protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiosuccinyl.

[0041] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and this description includes the instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but need not be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

[0042] In the chemical structure of the compounds described in the present disclosure, the bond does not specify a configuration, that is, if there is configurational isomerism in the chemical structure, the bond can be or simultaneously include both configurations.

[0043] While all of the above structural formulas are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates, and enantiomers. Detailed Description of the Invention

[0044] The present disclosure will be explained in detail below with reference to specific examples, so that those skilled in the art can more comprehensively understand the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0045] Example 1

[0046]

[0047] Step 1: Synthesis of Compound 2

[0048] Into a 3 L three-necked flask, add 100.00 g of L-glutamic acid and 1000 mL of isopropyl alcohol, and start stirring. Cool down to -20 °C, and slowly add dropwise 404.31 g of thionyl chloride. After the addition is complete, react at 20 - 25 °C for 15 h. Heat to 45 - 50 °C and continue to react for 24 h. After monitoring by TLC that the raw materials are completely converted, concentrate, add saturated sodium bicarbonate solution until there are no obvious bubbles in the system, extract with dichloromethane (500 mL * 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain Compound 2 (161 g, yield 95%), which is directly put into the next step.

[0049] Step 2: Synthesis of Compound 3

[0050] Into a 2 L three-necked flask, add 150.00 g of Compound 2 and 1000 mL of dichloromethane, and start stirring. Add 131.25 g of triethylamine. Slowly add dropwise 184.01 g of BOC anhydride. After the addition is complete, react at 20 - 25 °C for 15 h. After monitoring by TLC that the raw materials are completely converted, concentrate, dissolve in petroleum ether: ethyl acetate = 4:1 until clear, filter, and concentrate to obtain Compound 3 (198 g, yield 92%).

[0051] Step 3: Synthesis of Compound 4

[0052] Into a 3 L three-necked flask, add 100.00 g of Compound 3, add 600 mL of tetrahydrofuran, start stirring, and displace with nitrogen three times. Cool to -65 °C with dry ice-ethanol, and slowly add dropwise 664 mL of a LiHMDS (1 M in THF) solution. After the addition is complete, stir at -65 to -60 °C for 1 h. Add 22.79 g of neodymium(III) chloride, and stir at -65 to -60 °C for 1 h. Slowly add dropwise 39.81 g of bromoacetonitrile, and stir at -65 to -60 °C for 2.5 h. After monitoring by TLC that the raw materials are completely converted, add 800 mL of saturated ammonium chloride solution, concentrate to remove most of the tetrahydrofuran, extract with ethyl acetate (400 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by column chromatography to obtain Compound 4 (83.8 g, yield 75%).

[0053] Step 4: Synthesis of Compound 5

[0054] Into a 1 L three-necked flask, add 62.60 g of Compound 4, add 500 mL of acetonitrile, start stirring. Cool to 10 °C in an ice-water bath, add 6.27 g of DMAP, and slowly add dropwise 110.64 g of BOC anhydride. After the addition is complete, stir at 25 to 30 °C for 15 h. After monitoring by TLC that the raw materials are completely converted, concentrate and purify by column chromatography to obtain Compound 5 (74.9 g, yield 94%).

[0055] MS: 327.1 [M - Boc - iPr + H] + ,371.1 [M - Boc + H] + ,427.2 [M - iPr] + ;

[0056] HNMR (400 Hz, DMSO - d6): 4.85 - 4.96 (m, 3H), 2.72 - 2.85 (m, 2H), 2.64 - 2.69 (m, 1H), 2.18 (t, J = 7.2 Hz, 2H), 1.45 (s, 18H), 1.15 - 1.21 (m, 12H).

[0057] Step 5: Synthesis of Compound 6

[0058] Into a 250 mL three-necked flask, 5.02 g of Compound 5 was added. The flask was purged with nitrogen three times, and then 50 mL of tetrahydrofuran was added. Stirring was started. At 24 °C, 12.59 g of titanium tetraisopropoxide was added, and the temperature remained unchanged. After the addition was complete, the flask was purged with nitrogen three times. The temperature was lowered to -60 °C using dry ice-ethanol bath, and 64 mL of ethylmagnesium bromide (1 M in THF) solution was slowly added dropwise. After the addition was complete, the reaction was carried out at -60 to -50 °C for 1 h, then the temperature was raised to 5 to 10 °C and the reaction was continued for 13 h. After monitoring by TLC showed that the starting material was completely converted, 7.5 mL of boron trifluoride diethyl etherate was slowly added and stirred for 1 h. 100 mL of saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was obtained. The crude product was purified by column chromatography to obtain Compound 6 (2.36 g, yield 65%), and the optical purity was greater than 98%.

[0059] MS: 285.0 [M-tBu+H] + , 241.1 [M-Boc+H] + , 341.0 [M+H] + ;

[0060] HNMR (400 Hz, DMSO-d6): 7.72 (brs, 1H), 7.37 (brs, 1H), 4.86 - 4.92 (m, 1H), 3.87 - 3.92 (m, 1H), 2.50 - 2.55 (m, 1H), 1.96 - 2.07 (m, 2H), 1.85 - 1.91 (m, 1H), 1.59 - 1.65 (m, 1H), 1.38 (s, 9H), 1.17 (t, J = 6.6 Hz, 6H), 0.54 - 0.77 (m, 4H).

[0061] Since the present disclosure has been described in terms of its particular embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the present disclosure.

Claims

1. A method for preparing a compound of formula (IV) or a salt thereof, comprising: The step of preparing the compound shown in formula (IV) by reacting the compound shown in formula (V), wherein, R1 is selected from hydrogen, amino group and amino group protected by an amino protecting group, R2 is selected from hydrogen and a carboxyl protecting group, R3 is C 1-6 alkyl, 2. The preparation method according to claim 1, wherein the amino protecting group is selected from acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, formyl, benzoyl, phthaloyl, benzyl, trityl, 2,5-dimethylpyrrolyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl, preferably tert-butoxycarbonyl.

3. The preparation method according to claim 1 or 2, wherein the carboxyl protecting group is selected from methyl, ethyl, isopropyl, allyl, isopentenyl and trimethylsilylethyl, preferably methyl, ethyl, isopropyl.

4. The preparation method according to any one of claims 1-3, wherein R1 is -NHBoc or -N(Boc)2.

5. The preparation method according to any one of claims 1-4, wherein R3 is methyl, ethyl or isopropyl.

6. The preparation method according to any one of claims 1-5, wherein the Grignard reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, and preferably the molar ratio of the compound shown in formula (V) to the Grignard reagent is 1:1-1:

10.

7. The preparation method according to any one of claims 1-6, wherein the reaction is carried out in the presence of a catalyst, and the catalyst is Ti(i-PrO)4, Ti(i-PrO)3Cl, Ti(t-BuO)3Cl or Ti(t-BuO)4, and preferably the molar ratio of the compound shown in formula (V) to the catalyst is 1:1-1:

10.

8. The preparation method according to any one of claims 1-7, wherein R1 is -N(Boc)2, and the method further comprises the step of preparing the compound shown in formula (V) from the compound shown in formula (VI), wherein, R1’ is -NHBoc, 9. A preparation method of a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, comprising the preparation method of the compound shown in formula (IV) or a salt thereof according to any one of claims 1-8, 10. The compound shown in formula (V) or a salt thereof, Among them, R1 is selected from hydrogen, amino group and amino group protected by an amino protecting group, R2 is selected from hydrogen and a carboxyl protecting group, R3 is C 1-6 alkyl group.

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