Method for producing nitrogen-containing spirocyclic compound and compound thereof

Abstract

To provide a method for synthesizing a nitrogen-containing spirocyclic compound efficiently through a short process.SOLUTION: Provided is a method for producing a nitrogen-containing spirocyclic compound through a short process by a nitro-Mannich reaction between a cyclic ketone compound and a nitroalkylamine, and also provided is a compound thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a nitrogen-containing spirocyclic compound and the compound. [Background technology]

[0002] Various compounds with nitrogen-containing spiro ring structures are known as biologically active substances. For example, tuberindin, one of such spiro ring compounds, is a natural compound derived from truffles and is known to increase the expression levels of adenosine triphosphate (ATP)-binding cassette transporter G2 (ABCG2) and organic anion transporter 1 (OAT1), and may contribute to the improvement of hyperuricemia and gout (Non-Patent Document 1).

[0003] The chemical synthesis of nitrogen-containing spirocyclic compounds generally involves complex reaction pathways involving many steps (Patent Document 1, Non-Patent Document 2). There is a demand for the development of a new synthesis method that is efficient and can be realized in a short number of steps, which simplifies such complex synthesis pathways.

[0004] The Mannich reaction is known as an organic synthesis reaction that can synthesize compounds having complex structures in a few steps. The Mannich reaction is a reaction between a primary or secondary amine compound, a carbonyl compound (e.g., aldehyde, etc.), and a carbonyl compound having an α-hydrogen, and is a condensation reaction that occurs via an iminium ion. The nitroMannich reaction, which uses a nitro compound having an α-hydrogen instead of a carbonyl compound having an α-hydrogen, is also known (Non-Patent Documents 3, 4). However, there are no known examples of applying these reactions to the synthesis of nitrogen-containing spirocyclic compounds. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Patent Application Publication No. 2015 / 51407A1 [Non-patent literature]

[0006] [Non-Patent Document 1] Lan-Qin Zhao et al., Organic Letters 2022, 24, 4333-4337 [Non-Patent Document 2] Guiqing Xu et al., Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 10, pp. 1775-1778 [Non-Patent Document 3] James C. Anderson et al., Tetrahedron Letters 53 (2012) 5707-5710 [Non-Patent Document 4] Wannaporn Disadee et al., Organic & Biomolecular Chemistry, 2018, 16, 707-711 Summary of the Invention [Problem to be solved by the invention]

[0007] One of the problems to be solved by the present invention is to provide a method for efficiently synthesizing a nitrogen-containing spirocyclic compound in a short number of steps. [Means for solving the problem]

[0008] The present invention provides a method for producing a nitrogen-containing spirocyclic compound in a short process by the nitroMannich reaction of a cyclic ketone compound with a nitroalkylamine, and the compound.

[0009] In some embodiments, the compound of formula [Ia], [Ib], or [Ic]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, hydroxy, OR 5 , SH, C(=O)-R6 , CO2R 6 ,CONR 7 R 8 , C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-R 6 , C 1-6 Alkyl-CO2R 6 , C 1-6 Alkyl-NR 7 R 8 , C 1-6 Alkyl-SC 1-6 Alkyl, C 1-6 Alkyl-C(=O)-NR 7 R 8 , C 1-6 Alkyl-NR 6 -CH-(NR 7 R 8 )2, C 6-10 Aryl, C 6-10 Aryl-OR 6 or an aliphatic or aromatic 5- to 10-membered nitrogen-containing heterocyclic group, R 5 each independently, when there are more than one, is a hydroxy-protecting group; R 6 , R 7 , R 8 , and R X are each independently hydrogen or C 1-6 is alkyl, Ring A is C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, and C 1-6 Alkyl-OR 5 and wherein, when Ring A is a heterocycle, it contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. or a salt thereof, comprising the steps of: [ka] [In the formula, ring A is as defined above.] or a salt thereof and a compound represented by the formula [IIIa], [IIIb], or [IIIc]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , and R X is as above] or a salt thereof to obtain a compound represented by formula [Ia], [Ib], or [Ic], or a salt thereof.

[0010] In another embodiment, the compound of formula [Ia], [Ib], or [Ic]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X and Ring A is as described herein. or a salt thereof.

[0011] In yet another embodiment, the compound of formula [IVa], [IVb], or [IVc]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X , ring A, and a bond: [ka] are as described herein. or a salt thereof [However, tuberindin A and B are excluded] is provided.

[0012] In yet another embodiment, the compound of formula [IVa'], [IVb'], or [IVc']: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X and Ring A is as described herein. or a salt thereof. Effect of the Invention

[0013] In some embodiments, the present invention may have at least one of the following advantages. (1) A nitrogen-containing spirocyclic compound can be formed in a short step, preferably in one step. (2) The spiro ring formation reaction can be carried out under mild conditions. In one embodiment, it can be carried out at room temperature and / or without a solvent. In another embodiment, it can be carried out in the absence of a catalyst. (3) Since the structures of the cyclic ketone compound and the nitroalkylamine can be modified separately and easily before the spiro ring formation, a wide range of nitrogen-containing spiro ring compounds can be produced efficiently and simply. (4) The stereochemistry of nitrogen-containing spirocyclic compounds can be easily controlled by the nitroMannich reaction. (5) The nitrogen-containing spirocyclic compounds having a nitro group can be further modified to give various spirocyclic compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In the present specification, halogen includes, for example, fluorine, chlorine, bromine, and iodine, and is preferably chlorine or bromine.

[0015] In this specification, C 1-6 Alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.1-6 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and 3-ethylbutyl. C is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. 1-4 It is preferably an alkyl group, more preferably methyl or ethyl.

[0016] In this specification, C 6-10 Aryl means an aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 Aryl includes, for example, phenyl, 1-naphthyl, and 2-naphthyl, preferably phenyl.

[0017] In the present specification, the term "aliphatic or aromatic 5- to 10-membered nitrogen-containing heterocyclic group" refers to a monocyclic or bicyclic aliphatic or aromatic 5- to 10-membered heterocyclic group containing at least one nitrogen atom. Examples of the aliphatic 5- to 10-membered nitrogen-containing heterocyclic group include pyrrolidinyl, imidazolinyl, piperidinyl, azepanyl, azocanyl, azonanyl, morpholinyl, and thiazinyl. Examples of aromatic 5- to 10-membered nitrogen-containing heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, azocinyl, azonyl, indolyl, isoindolyl, benzimidazolyl, purinyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, oxazolyl, and thiazolyl.Preferably, aromatic 5- to 9-membered nitrogen-containing heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, and isoindolyl.More preferably, imidazolyl or indolyl.

[0018] In the present specification, the protecting group for hydroxy is not particularly limited as long as it is a protecting group commonly used in the art, and examples thereof include benzyl, p-methoxyphenylbenzyl, methoxymethyl, acetyl, benzoyl, trityl, and alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl). Preferred is alkylsilyl.

[0019] In the present specification, an aliphatic 4- to 7-membered carbocyclic ring means a monocyclic saturated or partially unsaturated hydrocarbon ring having 4 to 7 carbon atoms. Examples of the aliphatic 4- to 7-membered carbocyclic ring include cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, and cycloheptene. A 4- to 7-membered monocyclic saturated hydrocarbon ring is preferred.

[0020] In the present specification, the term "aliphatic 4- to 7-membered heterocycle" refers to a 4- to 7-membered monocyclic saturated or partially unsaturated heterocycle containing at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of the aliphatic 4- to 7-membered heterocycle include azetidine, oxetane, thietane, diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, tetrahydropyran, tetrahydrothiopyran, diazacyclohexane, piperazine, morpholine, tetrahydrooxazine, thiomorpholine, dioxane, azepane, oxepane, diazepane, oxazepane, dioxepane, and thiazepane. Preferably, the heterocycle is a 4- to 7-membered monocyclic saturated heterocycle. More preferred are aliphatic 5- to 6-membered oxygen-containing heterocycles, such as tetrahydrofuran, dioxolane, tetrahydropyran, and dioxane, and even more preferred is tetrahydrofuran.

[0021] In the present specification, the salt of a compound is not particularly limited as long as it is a salt formed with the compound. Examples of the salt include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases.

[0022] In this specification, the dehydrating agent means a reagent used in the reaction between a cyclic ketone compound and a nitroalkylamine, which is a spiro ring forming reaction. The dehydrating agent is not particularly limited as long as it is a dehydrating agent used in a dehydration condensation reaction such as the Mannich reaction, and examples thereof include sodium sulfate, magnesium sulfate, magnesium oxide, potassium carbonate, calcium chloride, calcium oxide, and desiccants (e.g., molecular sieves, silica gel, and alumina). Desiccants are preferred. Molecular sieves are more preferred.

[0023] As used herein, room temperature means uncontrolled ambient temperature, such as 0° C. to 40° C. Reaction temperatures include the stated temperature ±5° C. unless otherwise specified.

[0024] As used herein, tuberindins include tuberindins A and B. [ka]

[0025] In some embodiments, R 1 is C 6-10 Aryl, C 6-10 Aryl-OH, or an aromatic 5- or 9-membered monocyclic or bicyclic nitrogen-containing heterocyclic group.

[0026] In some embodiments, R 2 CO2R 6 It is.

[0027] In some embodiments, R 3 is hydrogen.

[0028] In some embodiments, R X is hydrogen or C 1-4 It is an alkyl.

[0029] In some embodiments, a method for producing a compound represented by formula [Ib] or a salt thereof is provided.

[0030] In another embodiment, a method for producing a compound represented by formula [Ic] or a salt thereof is provided.

[0031] In some embodiments, R 1’ is hydrogen, or a salt thereof.

[0032] In another embodiment, R 1’ is hydrogen and R 2 CO2R 6The present invention provides a compound represented by formula [Ia], [Ib], or [Ic], or a salt thereof, wherein

[0033] In yet another embodiment, R 1’ is hydrogen and R 2 CO2R 6 and ring A is hydroxy C 1-6 Alkyl or C 1-6 Alkyl-OR 5 The compound or a salt thereof represented by formula [Ia], [Ib], or [Ic] is an aliphatic 5- to 6-membered oxygen-containing heterocycle substituted with

[0034] In some embodiments, there is provided a compound represented by formula [IVa] or a salt thereof.

[0035] In another embodiment, the compound of formula [IVa] is tuberindin A or B, or the following formula: [ka] The present invention provides a method for producing a compound represented by formula [IVa] or a salt thereof,

[0036] Manufacturing method Methods for producing the compound of formula [Ia], [Ib], or [Ic] are exemplified below. The compound obtained in each step may be appropriately isolated and purified by a known method commonly used in the art, such as distillation, recrystallization, column chromatography, etc., or may proceed to the next step without isolation or purification.

[0037] Manufacturing method 1A [ka] [In the formula, each symbol is as defined herein]

[0038] A compound represented by formula [II] or a salt thereof can be reacted with a compound represented by formula [IIIa] or a salt thereof in the presence or absence of a catalyst to obtain a compound represented by formula [Ia] or a salt thereof. This step may preferably proceed by the nitroMannich reaction, in which the carbonyl carbon of the compound represented by formula [II] reacts with the amino group of the compound represented by formula [IIIa] to form an iminium ion through dehydration, and then the carbanion generated at the α-carbon of the nitro group in the reaction system undergoes an intramolecular addition reaction with the iminium ion to form a spiro ring compound represented by formula [Ia]. Examples of catalysts that can be used in this step include acetic acid, trifluoroacetic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, ion exchange resins (e.g., Dowex®), and ammonium acetate. The reaction may preferably proceed in the absence of a catalyst. This step may be carried out in the presence of a dehydrating agent. Examples of the dehydrating agent include sodium sulfate, magnesium sulfate, magnesium oxide, potassium carbonate, calcium chloride, calcium oxide, and desiccants (e.g., molecular sieves, silica gel, and alumina). Desiccants are preferred. Molecular sieves are more preferred. Molecular sieves 3A, 4A, or 5A are even more preferred. This step may be carried out in a solvent commonly used in the art or without a solvent, such as dichloromethane, chloroform, toluene, benzene, acetonitrile, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, methanol, and ethanol. The reaction temperature in this step may be, for example, room temperature. The resulting compound represented by formula [Ia] or a salt thereof may be used in the next step without purification.

[0039] Manufacturing method 1B [ka] [In the formula, each symbol is as defined herein]

[0040] According to the same procedure as in Production Method 1A, a compound represented by formula [II] or a salt thereof can be reacted with a compound represented by formula [IIIb] or a salt thereof to obtain a compound represented by formula [Ib] or a salt thereof.

[0041] Manufacturing method 1C [ka] [In the formula, each symbol is as defined herein]

[0042] According to the same procedure as in Production Method 1A, a compound represented by formula [II] or a salt thereof can be reacted with a compound represented by formula [IIIc] or a salt thereof to obtain a compound represented by formula [Ic] or a salt thereof.

[0043] Manufacturing method 2 [ka] [In the formula, each symbol is as defined herein] The compounds represented by formulae [Ia], [Ib], and [Ic] or salts thereof obtained by the preparation methods 1A, 1B, and 1C can be oxidized in the presence of a base (e.g., Nef reaction) to obtain the compounds represented by formulae [IVa], [IVb], and [IVc] or salts thereof. That is, the compounds represented by formulae [Ia], [Ib], and [Ic] or salts thereof may be used as preparation intermediates to prepare the compounds represented by formulae [IVa], [IVb], and [IVc] or salts thereof. In this step, the α hydrogen of the nitro group of the compound represented by formula [Ia], [Ib], or [Ic] is deprotonated by a base to produce a carbanion, which is converted to a carbonyl group by an oxidizing agent to obtain the compound represented by formula [IVa], [IVb], or [IVc]. Bonds of the compounds represented by formulae [IVa], [IVb], and [IVc]: [ka] may be converted to a double bond by the reaction in this step. Examples of the base used in this step include sodium alkoxides (e.g., sodium methoxide, sodium ethoxide, and sodium tert-butoxide), potassium alkoxides (e.g., potassium methoxide, potassium ethoxide, and potassium tert-butoxide), sodium hydride, sodium carbonate, sodium phosphate, sodium hexamethyldisilazide, potassium carbonate, potassium phosphate, potassium hexamethyldisilazide, lithium hexamethyldisilazide, potassium fluoride, sodium fluoride, cesium fluoride, cesium carbonate, triethylamine, and diazabicycloundecene. This step may be carried out in the presence of an oxidizing agent, such as oxygen, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, sodium hypochlorite, cerium ammonium nitrate, cerium ammonium sulfate, dichlorodicyanoquinone, copper(II) acetate, copper(II) bromide, copper(II) chloride, silver(I) oxide, and silver(I) acetate. This step may be carried out in a solvent commonly used in the art, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, ethyl acetate, methanol, and ethanol. The reaction temperature in this step may be, for example, room temperature.

[0044] As an alternative to this production method, the nitro group of the compounds of formulae [Ia], [Ib], and [Ic] may be converted to an oxime by a reduction reaction, and then the compounds of formulae [IVa], [IVb], and [IVc] or salts thereof may be obtained by hydrolysis.

[0045] Manufacturing method 2' [ka] [In the formula, each symbol is as defined herein] The compounds represented by formulae [Ia], [Ib], and [Ic] or salts thereof obtained by the production methods 1A, 1B, and 1C can be reacted by reduction to obtain the compounds represented by formulae [IVa'], [IVb'], and [IVc'] or salts thereof. The reduction reaction may be carried out in the presence of a catalyst and an acid. Examples of the catalyst include zinc, iron, nickel, and palladium. Examples of the acid include hydrochloric acid and acetic acid. The reaction temperature in this step may be, for example, room temperature.

[0046] Manufacturing method 3 The compound of formula [IVa], [IVb], [IVc], [IVa'], [IVb'], or [IVc'] obtained by the production method 2 or 2' or a salt thereof may have a hydroxy-protecting group R 5 If the fluoride has the formula (I), it may be further subjected to a deprotection reaction. The deprotection reaction may be carried out in a solvent in the presence of a base. Examples of the base include tetra-n-butylammonium fluoride, sodium hydroxide, potassium hydroxide, potassium fluoride, cesium fluoride, and sodium fluoride. Examples of the solvent include tetrahydrofuran, dimethylformamide, dimethylacetamide, methanol, ethanol, propanol, butanol, and water.

[0047] Manufacturing method 4 The compound represented by formula [II] or a salt thereof may be a commercially available compound, or may be obtained by reacting it according to a known method. For example, the compound represented by formula [II] or a salt thereof in which ring A is an aliphatic 4- to 7-membered carbon ring or heterocycle (e.g., tetrahydrofuran ring) can be obtained by introducing a hydroxyl group into any position of the ring structure (e.g., tetrahydrofuran ring) and subjecting it to an oxidation reaction in the presence of a base.

[0048] Manufacturing method 5 The compound of formula [IIIa], [IIIb], or [IIIc] or a salt thereof may be a commercially available compound, or may be obtained by reacting it according to a known method. For example, the compound of formula [IIIa] or a salt thereof may be produced according to the following reaction. [ka] [In the formula, R′ and R″ are each independently hydrogen, C 1-6 alkyl, or phenyl, or R′ and R″ together with the carbon to which they are attached and the alpha nitrogen thereof may form a fluorenylidene group, with other symbols as defined herein. The compound of formula [Va] and the compound of formula [VIa] can be subjected to, for example, Michael addition reaction to obtain the compound of formula [VIIa], which can then be reacted in the presence of an acid to obtain the compound of formula [IIIa]. The acid can be, for example, hydrochloric acid. The solvent can be, for example, tetrahydrofuran. The reaction temperature in either step can be, for example, room temperature.

[0049] Some specific embodiments of the present invention are illustrated below. Item 1. Formula [Ia], [Ib], or [Ic]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, hydroxy, OR 5 , SH, C(=O)-R 6 , CO2R 6 ,CONR 7 R 8 , C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-R 6 , C 1-6 Alkyl-CO2R 6 , C 1-6 Alkyl-NR 7 R8 , C 1-6 Alkyl-SC 1-6 Alkyl, C 1-6 Alkyl-C(=O)-NR 7 R 8 , C 1-6 Alkyl-NR 6 -CH-(NR 7 R 8 )2, C 6-10 Aryl, C 6-10 Aryl-OR 6 or an aliphatic or aromatic 5- to 10-membered nitrogen-containing heterocyclic group, R 5 each independently, when there are more than one, is a hydroxy-protecting group; R 6 , R 7 , R 8 , and R X are each independently hydrogen or C 1-6 is alkyl, Ring A is C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, and C 1-6 Alkyl-OR 5 and wherein, when Ring A is a heterocycle, it contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. or a salt thereof, comprising the steps of: [ka] [In the formula, ring A is as defined above.] or a salt thereof and a compound represented by the formula [IIIa], [IIIb], or [IIIc]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , and R Xis as above] or a salt thereof to obtain a compound represented by formula [Ia], [Ib], or [Ic] or a salt thereof.

[0050] Item 2. Further, the compound represented by formula [Ia], [Ib], or [Ic] or a salt thereof is oxidized to obtain a compound represented by formula [IVa], [IVb], or [IVc]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X and ring A is as described in item 1, and the bond: [ka] is a single bond or a double bond, However, when the bond is a double bond, R 1’ does not exist] or a salt thereof.

[0051] Item 2'. Further, the compound represented by formula [Ia], [Ib], or [Ic] or a salt thereof may be reduced to obtain a compound represented by formula [IVa'], [IVb'], or [IVc']: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X and ring A is as described in item 1. or a salt thereof.

[0052] Item 3. The method according to item 1, 2, or 2', wherein the reaction of the compound represented by formula [II] or a salt thereof with the compound represented by formula [IIIa], [IIIb], or [IIIc] or a salt thereof is carried out in the presence of a dehydrating agent.

[0053] Section 4.R 2 is C(=O)-R 6 , CO2R 6 , or C 1-6 Alkyl-C(=O)-R 6 The method according to any one of items 1 to 3 and 2',

[0054] Item 5. Ring A is hydroxy C 1-6 Alkyl or C 1-6 Alkyl-OR 5 The method according to any one of items 1 to 4 and 2', wherein R is an aliphatic 4- to 7-membered heterocycle optionally substituted by

[0055] Item 6. Ring A is hydroxy C 1-6 Alkyl or C 1-6 Alkyl-OR 5 The method according to any one of items 1 to 5 and 2', wherein the ring is an aliphatic 5- to 6-membered oxygen-containing heterocycle substituted with

[0056] Item 7. Ring A is hydroxy C 1-6 Alkyl or C 1-6 Alkyl-OR 5 The method according to any one of items 1 to 6 and 2', wherein the tetrahydrofuran is substituted with

[0057] Section 8.R 1 C 6-10 Aryl, C 6-10 Aryl-OR 6 or an aromatic 5- to 10-membered nitrogen-containing heterocyclic group.

[0058] Section 9.R 1 C 6-10 Aryl, C 6-10The method according to any one of items 1 to 8 and 2', wherein the aryl group is aryl-OH, or an aromatic 5- to 9-membered nitrogen-containing heterocyclic group.

[0059] Section 10.R 1 The method according to any one of paragraphs 1 to 9 and 2', wherein is phenyl, hydroxyphenyl, imidazolyl, or indolyl.

[0060] Section 11.R 1 The method according to any one of items 1 to 10 and 2', wherein is phenyl or imidazolyl.

[0061] Section 12.R X The method according to any one of paragraphs 1 to 11 and 2', wherein is hydrogen.

[0062] Item 13. The method according to any one of items 2 to 12 and 2', wherein the bond is a double bond.

[0063] Item 14. The method according to any one of items 1 to 13 and 2', for producing a compound represented by formula [Ia] or a salt thereof.

[0064] Item 15. After oxidizing the compound represented by formula [Ia], [Ib], or [Ic] or a salt thereof, a protecting group R 5 The method according to any one of items 1 to 14 and 2', comprising removing

[0065] Item 16. Formula [Ia], [Ib], or [Ic]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X and ring A is as described in item 1. or a salt thereof.

[0066] Item 17. Formula [IVa], [IVb], or [IVc]: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X , ring A, and a bond: [ka] is as described in item 1 or 2. or a salt thereof [However, tuberindins A and B are excluded.]

[0067] Item 18. Formula [IVa'], [IVb'], or [IVc']: [ka] [In the formula, R 1 , R 1’ , R 2 , R 3 , R 4 , R X and ring A is as described in item 1. or a salt thereof.

[0068] The specific aspects and options exemplified in this specification can be arbitrarily combined, so long as they are combinable and not contradictory, and such combined aspects are also included within the scope of the present invention.

[0069] The following abbreviations may be used in this specification: B2pin2: Bis(pinacolato)diboron DBU: Diazabicycloundecene DCM: dichloromethane DMF: Dimethylformamide DMP: Dess-Martin periodinane LiOTf: Lithium trifluoromethanesulfonate TBAF: Tetra-n-butylammonium fluoride TIPS: Triisopropylsilyl THF: tetrahydrofuran EXAMPLES

[0070] The present invention will be described in more detail below by way of examples, but the present invention is not limited to these.

[0071] The measuring device used in this example is shown below. NMR: JEOL ECS-400 Mass spectrometry: Thermo Fisher Scientific MS Exactive Plus HPLC UltiMate 3000 (ESI)

[0072] Example 1: Preparation of 5-substituted-3-oxo-tetrahydrofuran [6] (1) Process 1 [ka] (S)-Tetrahydrofuran-2-carboxylic acid [1] (11.6 g, 100 mmol, Tokyo Chemical Industry) was dissolved in CHCl (90 mL) under an argon atmosphere, and BH·SMe (11.4 g, 150 mmol, Sigma-Aldrich) was added dropwise over 30 min at 0°C. After stirring at room temperature for 12 h, 2M aqueous NaOH (200 mL) was carefully added dropwise and the mixture was extracted with diethyl ether. The organic layer was dried over NaSO, filtered, and the solvent was removed by distillation to give compound [2] as a colorless oil (7.66 g, 75% yield). This compound was used in the next step without purification. R f 0.25 [n-hexane / EtOAc (50:50)]. 1H NMR (400 MHz, CDCl3): δ 4.06-3.97 (m, 1H), 3.91-3.82 (m, 1H), 3.83-3.75 (m, 1H), 3.68 (dd, J = 11.5, 3.2 Hz, 1H), 3.50 (dd, J = 11.6, 6.2 Hz, 1H), 1.98-1.82 (m, 3H), 1.69-1.59 (m, 1H).

[0073] (2) Process 2 [ka] Triisopropylsilyl chloride (5.78 g, 6.4 mL, 30 mmol) was added dropwise to a solution of (S)-(tetrahydrofuran-2-yl)methanol [2] (2.55 g, 25.0 mmol) and imidazole (4.25 g, 62.5 mmol) in CHCl (40 mL) at 0°C, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the crude product was purified by medium pressure silica gel column chromatography [n-hexane / EtOAc (80:20)]. Compound [3] was obtained as a colorless oil (6.20 g, 96% yield). R f 0.85 [n-hexane / EtOAc (80:20)]. 1 H NMR (400 MHz, CDCl3): δ 4.03-3.94 (m, 1H), 3.89-3.81 (m, 1H), 3.80-3.73 (m, 1H), 3.72 (dd, J = 9.9, 4.7 Hz, 1H), 3.62 (dd, J = 10.2, 5.5 Hz, 1H), 2.02-1.69 (m, 4H), 1.14-1.00 (m, 21H).

[0074] (3) Process 3 [ka] In a glove box under nitrogen, [Ir(cod)OMe]2 (41 mg, 0.13 mmol), 2-methyl-1,10-phenanthroline (25 mg, 0.25 mmol), B2pin2 (1.9 g, 7.5 mmol), compound [3] (646 mg, 2.5 mmol), and cyclooctane (2.0 mL) were added to a 15 mL vial. The vial was sealed with a cap and stirred at 100 °C for 24 h in a preheated aluminum block heater. After the reaction was complete, the mixture was diluted with THF (25 mL) and transferred to a flask containing NaBO3·4H2O (4.6 g, 30 mmol) and water (25 mL) and stirred at room temperature for 12 h. The organic layer was separated and the aqueous phase was extracted with EtOAc (3 times, 30 mL each time). The combined organic layers were dried over NaSO4, suction filtered, and concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 (20 mL) and DMP (2.1 g, 5.0 mmol) was added at 0° C. After stirring at room temperature for 12 hours, the reaction mixture was concentrated and purified by medium pressure silica gel column chromatography [n-hexane / EtOAc (90:10)] to give compound [6] as a colorless oil (238 mg, 35% yield). R f 0.70 [n-hexane / EtOAc (80:20)]. 1 H NMR (400 MHz, CDCl3): δ 4.51-4.44 (m, 1H), 4.12 (d, J = 16.7 Hz, 1H), 4.01 (dd, J = 10.8, 3.1 Hz, 1H), 3.92 (d, J = 16.7 Hz, 1H), 3.81 (dd, J = 10.8, 3.0 Hz, 1H), 2.61-2.48 (m, 2H), 1.16-0.99 (m, 21H).

[0075] Example 2: Preparation of nitroalkylamine compound

[10] [ka] trans-β-nitrostyrene [7] (13.4 g, 50 mmol), LiOTf (0.78 g, 5.0 mmol), and ethyl diphenylmethyleneiminoacetate [8] (8.95 g, 60 mmol) were stirred in dry THF (50 mL), and a solution of DBU (0.75 mL, 5.0 mmol) in dry THF (50 mL) was added. After stirring at room temperature for 6 hours, the mixture was diluted with THF (100 mL), and 1M HCl (400 mL) was added at 0°C and stirred at room temperature for 12 hours. After removing THF under reduced pressure, the aqueous layer was washed with ether (3 times, 200 mL each time) and neutralized with NaHCO3. The aqueous layer was extracted with CH2Cl2 (3 times, 500 mL each time), and the combined organic layers were dried over Na2SO4, filtered with suction, and concentrated under reduced pressure. The crude product was then purified by medium pressure silica gel column chromatography [n-hexane / EtOAc (50:50)] to obtain compound

[10] as a yellow oil (7.40 g, 58% yield). R f 0.2 [n-hexane / EtOAc (80:20)]. 1 H NMR (400 MHz, CDCl3): δ 7.37 - 7.15 (m, 5H), 5.06 (dd, J = 13.3, 5.6 Hz, 1H), 4.75 (dd, J = 13.3, 9.0 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 3.78 (td, J = 8.5, 5.5 Hz, 1H), 3.64 (d, J = 8.1 Hz, 1H), 1.02 (t, J = 7.1 Hz, 3H).

[0076] Example 3: Preparation of tuberindin (1) Step 1 (NitroMannich reaction) [ka] Compound

[10] (757 mg, 3.0 mmol) and activated molecular sieve 4A (1.0 g) were stirred in a 15 mL vial, and then compound [6] (163 mg, 0.60 mmol) was added and stirred at room temperature for 48 hours. After the reaction was completed, the solid was filtered off and purified by medium pressure silica gel column chromatography [silica gel, n-hexane / EtOAc (90:10)] to obtain spirocyclic compound

[11] as a colorless oil (119 mg, 39% yield). R f 0.50 [n-hexane / EtOAc (80:20)]. 1 H NMR (400 MHz, C6D6): δ 7.07-6.94 (m, 5H), 4.95 (d, J = 7.8 Hz, 1H), 4.30 (t, J = 8.0 Hz, 1H), 4.00-3.88 (m, 2H), 3.85-3.69 (m, 3H), 3.64-3.56 (m, 1H), 3.02 (brs, 1H), 2.16 (dd, J = 12.8, 6.5 Hz, 1H), 1.99 (dd, J = 12.8, 8.3 Hz, 1H), 1.18-0.99 (m, 21H), 0.74 (t, J = 7.1Hz, 3H). HRMS (ESI) m / z: [M + H] + Calcd. for C 26 H 43 N2O6Si, 507.2890; Found, 507.2887.

[0077] (2) Step 2 (Neph reaction) [ka] DMF (1 mL) and compound

[11] (50 mg, 0.10 mmol) were added to a 4 mL vial, the mixture was frozen and degassed with liquid nitrogen, and the atmosphere in the vial was replaced with oxygen gas. To the resulting oxygen-saturated solution, 3.0 M tBuOK solution in DMF (0.10 mL, 0.30 mmol) was added at room temperature under oxygen atmosphere, and the mixture was stirred for 2 h. Saturated aqueous ammonium chloride solution (1.0 mL) was added followed by 1 M HCl, and the mixture was extracted with ethyl acetate (5 times, 2 mL each time). The combined organic layer was dried over NaSO4, suction filtered and concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography [silica gel, n-hexane / EtOAc (80:20)], and after extraction from the silica gel with methanol, compound

[12] was obtained as a green oily substance (5.0 mg, 10% yield). Compound

[12] was obtained as a mixture of ethyl ester and methyl ester due to partial solvolysis of its ester group (ethyl:methyl = 1:6). R f 0.40 [n-hexane / EtOAc (80:20)]. 1 H NMR (400 MHz, CDCl3): δ 7.43-7.30 (m, 5H), 6.82 (brs, 1H), 4.47-4.38 (m, 1H), 4.28 (qd, J = 7.2, 2.7 Hz, 0.28H), 4.05 (d, J = 8.9 Hz, 1H), 4.02 (dd, J = 11.3, 2.2 Hz, 1H), 3.87 (d, J = 8.9 Hz, 1H), 3.81 (s, 2.6H), 3.74 (dd, J = 11.2, 2.2 Hz, 1H), 2.67 (dd, J = 13.2, 9.7 Hz, 1H), 2.20 (dd, J = 8.6, 1.9 Hz, 1H), 1.30-1.08 (m, 21H+0.43H). HRMS (ESI) m / z: [M + H] + Calcd. for C 26 H 40 NO5Si, 474.2676; Found, 474.2674 (for ethyl ester); [M + H] + Calcd. for C26 H 40 NO5Si, 460.2519; Found, 460.2518 (for methyl ester).

[0078] (3) Process 3 [ka] Compound

[12] (2.6 mg, 5.0 μmol) in THF solution (0.5 mL) was added with 0.1M THF solution of tetrabutylammonium fluoride (0.13 mL, 12.5 μmol) and stirred at room temperature for 3 hours. After concentration under reduced pressure, the mixture was purified by flash chromatography [silica gel, EtOAc] to give compound

[13] as a green oil (1.2 mg, 76% yield). R f 0.40 [EtOAc]. 1 H NMR (400 MHz, CDCl3): δ 7.39- 7.24 (m, 5H), 7.09 (brs, 1H), 4.51-4.43 (m, 1H), 4.29 (q, J = 7.1 Hz, 0.28H), 4.09 (d, J = 9.1 Hz, 1H), 4.00 (dd, J = 11.8, 2.3 Hz, 1H), 3.93 (d, J = 9.0 Hz, 1H), 3.83 (s, 2.6H), 3.64 (d, J = 11.7 Hz, 1H), 2.71 (dd, J = 13.4, 9.6 Hz, 1H), 2.19-2.09 (m, 1H), 1.21 (t, J = 7.1Hz, 0.43H). HRMS (ESI) m / z: [M + Na] + Calcd. for C 17 H 19 NO5Na, 340.1161; Found, 340.1157 (for ethyl ester); [M + H] + Calcd. for C 26 H 40NO5Si, 326.1004; Found, 326.1000 (for methyl ester).

[0079] (4) Process 4 [ka] A solution of compound

[13] (1.2 mg, 3.8 μmol) in THF (0.5 mL) was added with 0.1 M aqueous NaOH (0.2 mL) and stirred at room temperature for 1 h. The reaction mixture was washed with diethyl ether (2 times, 2 mL each), neutralized with hydrochloric acid, and extracted with EtOAc (5 times, 2 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound

[14] as a green solid (1.0 mg, 89%). R f 0.40 [EtOAc / MeOH (90:10)]. 1 H NMR (400 MHz, DMSO-d6): δ 8.88 (s, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 4.90 (brs, 1H), 4.21-4.09 (m, 1H), 3.89 (d, J = 8.8 Hz, 1H), 3.61 (d, J = 8.8 Hz, 1H), 2.26 (dd, J = 13.0, 8.1 Hz, 1H), 1.96-1.87 (m, 1H). The two protons at 3.51 and 3.56 ppm are overlapped by water and are not observed. HRMS (ESI) m / z: [M + H] + Calcd. for C 15 H 16 NO5, 290.1028; Found, 290.1022. [Industrial Applicability]

[0080] The method for producing a nitrogen-containing spirocyclic compound provided in the present specification is applicable to the production of various nitrogen-containing spirocyclic compounds and is also industrially applicable, and is therefore expected to be useful for the production of many physiologically active substances.

Claims

1. Formula [Ia], [Ib], or [Ic]: 【Chemistry 1】 [In the formula, R １ , R １’ , R ２ , R ３ , and R ４ are each independently hydrogen, halogen, hydroxy, OR ５ , SH, C(=O)-R ６ , CO ２ R ６ , C.O.R. ７ R ８ , C １－６ Alkyl, Hydroxy C １－６ Alkyl, C １－６ Alkyl-C(=O)-R ６ , C １－６ Alkyl-CO ２ R ６ , C １－６ Alkyl-NR ７ R ８ , C １－６ Alkyl-S-C １－６ Alkyl, C １－６ Alkyl-C(=O)-NR ７ R ８ , C １－６ Alkyl-NR ６ -CH-(NR ７ R ８ ) ２ , C ６－１０ Aryl, C ６－１０ Aryl-OR ６ or an aliphatic or aromatic 5- to 10-membered nitrogen-containing heterocyclic group, R ５ each independently, when there are more than one, is a hydroxy-protecting group; R ６ , R ７ , R ８ , and R Ｘ are each independently hydrogen or C １－６ is alkyl, Ring A is C １－６ Alkyl, Hydroxy C １－６ Alkyl, and C １－６ Alkyl-OR ５ and wherein, when Ring A is a heterocycle, it contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. or a salt thereof, comprising the steps of: 【Chemistry 2】 wherein ring A is as defined above. or a salt thereof and a compound represented by the formula [IIIa], [IIIb], or [IIIc]: 【Chemistry 3】 [In the formula, R １ , R １’ , R ２ , R ３ , R ４ , and R Ｘ is as above] or a salt thereof to obtain a compound represented by formula [Ia], [Ib], or [Ic] or a salt thereof.

2. Further, the compound represented by formula [Ia], [Ib], or [Ic] or a salt thereof may be oxidized to obtain a compound represented by formula [IVa], [IVb], or [IVc]: 【Chemistry 4】 [In the formula, R １ , R １’ , R ２ , R ３ , R ４ , R Ｘ and ring A is as described in claim 1, and the bond: 【Chemistry 5】 is a single bond or a double bond, However, when the bond is a double bond, R １’ does not exist] 2. The method of claim 1, comprising obtaining a compound represented by the formula:

3. The method according to claim 1, wherein the reaction of the compound represented by formula [II] or a salt thereof with the compound represented by formula [IIIa], [IIIb], or [IIIc] or a salt thereof is carried out in the presence of a dehydrating agent.

4. R ２ is C(=O)-R ６ , CO ２ R ６ , or C １－６ Alkyl-C(=O)-R ６ The method of claim 1, wherein

5. Ring A is hydroxy C １－６ Alkyl or C １－６ Alkyl-OR ５ The method of claim 1 , wherein R is an aliphatic 4- to 7-membered heterocycle, optionally substituted with

6. Ring A is hydroxy C １－６ Alkyl or C １－６ Alkyl-OR ５ The method of claim 1 , wherein the ring is an aliphatic 5- to 6-membered oxygen-containing heterocycle substituted with

7. Ring A is hydroxy C １－６ Alkyl or C １－６ Alkyl-OR ５ 2. The method of claim 1 , wherein the substituted tetrahydrofuran is

8. R １ C ６－１０ Aryl, C ６－１０ Aryl-OR ６ or an aromatic 5- to 10-membered nitrogen-containing heterocyclic group.

9. R １ 2. The method of claim 1 , wherein is phenyl, hydroxyphenyl, imidazolyl, or indolyl.

10. R １ The method of claim 1 , wherein is phenyl or imidazolyl.

11. R Ｘ The method of claim 1 , wherein is hydrogen.

12. The method of claim 2 , wherein the bond is a double bond.

13. The method according to claim 1, for producing a compound represented by formula [Ia] or a salt thereof.

14. Formula [Ia], [Ib], or [Ic]: 【Chemistry 6】 [In the formula, R １ , R １’ , R ２ , R ３ , R ４ , R Ｘ and ring A is as defined in claim 1. or a salt thereof.

15. Formula [IVa], [IVb], or [IVc]: 【Chemistry 7】 [In the formula, R １ , R １’ , R ２ , R ３ , R ４ , R Ｘ , ring A, and a bond: 【Chemistry 8】 is as defined in claim 1 or 2. or a salt thereof [However, tuberindins A and B are excluded].

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