Method for preparing single-substituted bicyclo [1.1. 1] pentane derivative

Abstract

The present invention provides a process for the preparation of a compound of formula V, characterized in that it comprises the steps (S1) and (S2): # imgabs0 # (S1) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV, (S2) reacting the compound of formula IV obtained from step (S1) with an electrophilic reagent to obtain a compound of formula V wherein R1, R2, R3, R4, R5 are independently selected from hydrogen or C1-20 alkyl, or a group that breaks at least the bond prior to the aromatic ring to the carbonyl group, and wherein R6 is hydrogen. The raw materials required by the synthesis method are available on the market, and the reaction steps are simple, easy to operate, safe and efficient, and can be used for industrial large-scale production.

Description

Technical Field

[0001] The present application relates to the technical field of synthesis methods of bicyclo[1.1.1]pentane compounds (BCP), and in particular to a method for preparing a monosubstituted bicyclo[1.1.1]pentane derivative. Background Art

[0002] In recent years, bicyclo[1.1.1]pentane compounds have attracted much attention in materials science and drug research and are very popular intermediate compounds, thanks to their unique three-dimensional structure. In drug development, their rich SP 3 Hybridization and a size similar to that of a benzene ring allow it to be used as a bioisostere to replace the alkynyl or tert-butyl group or the aromatic ring of a planar structure in a drug molecule, thereby significantly improving the water solubility and stability of the drug and enhancing the applicability of the drug molecule. In materials science, bicyclo[1.1.1]pentane has been used in polymers, liquid crystals, monolayers and supramolecular structures due to its rigidity, chemical stability, transparency and thermal stability. Among them, bicyclo[1.1.1]pentane-1-carboxylic acid is an important member, which can conveniently and efficiently introduce bicyclo[1.1.1]pentane structures into drug or material molecules. In recent basic research, it was found that 2-substituted bicyclo[1.1.1]pentane derivatives can be successfully obtained by photocatalytic oxidation of bicyclo[1.1.1]pentane-1-carboxylic acid (J.Am.Chem.Soc.2023,145,3092-3100). Compared with the more common 1,3-substituted bicyclo[1.1.1]pentane derivatives, C2-substituted derivatives are more scarce and precious. Therefore, it is particularly important to prepare a large dose of the starting material that can synthesize it, bicyclo[1.1.1]pentane-1-carboxylic acid. However, the current methods for preparing bicyclo[1.1.1]pentane-1-carboxylic acid are very limited, and strict requirements are placed on the reactants and reaction conditions. The preparation methods in the prior art can usually only obtain low yields. There are two main known synthesis methods:

[0003] The first method is to irradiate [1.1.1] propellerane with oxalyl chloride to generate a mixture of bicyclo[1.1.1]pentane-1-yl chloride and bicyclo[1.1.1]pentane-2-yl chloride, and then hydrolyze the mixture to obtain bicyclo[1.1.1]pentane-1-carboxylic acid (J.Org.Chem.1970,35,2,369–373). However, the photoreaction is unstable, and the target product is a mixture, which is difficult to separate, so this method is difficult to be applied industrially.

[0004] The second method is to react [1.1.1] propellerane with methyl formate to generate [1.1.1] pentane-1-carboxylic acid, and then hydrolyze to obtain the target product (J. Am. Chem. Soc. 1992, 114, 601-620). However, the yield of this synthetic route is only 16%, and bicyclo[1.1.1] pentane-1-carboxylic acid cannot be efficiently generated.

[0005] Therefore, it is necessary to study new and efficient methods for the synthesis of bicyclo[1.1.1]pentane-1-carboxylic acid. Summary of the invention

[0006] In order to solve the above problems, in a first aspect of the present invention, a method for preparing a compound of formula IV is provided, the method comprising step (S1):

[0007]

[0008] (S1) reacting the compound of formula II with the compound of formula III to obtain a compound of formula IV, wherein R1, R2, R3, R4, and R5 are independently selected from hydrogen or C1 -20 Alkyl, and wherein R6 is hydrogen.

[0009] By means of the above method, bicyclo[1.1.1]pentane-1-carboxylic acid and its derivatives can be synthesized. In the method according to the present invention, [1.1.1] propellerane is used as the initial raw material, and the target product bicyclo[1.1.1]pentane-1-carboxylic acid or its derivatives is obtained under stable and mild conditions through two-step reactions of addition and cracking (substitution). The raw materials required for the synthesis method are commercially available and each step of the reaction is simple and easy to operate. Therefore, the synthesis method according to the present invention is safe and efficient and can be used for industrial scale-up production.

[0010] In some embodiments, R1, R2, R3, R4, and R5 are independently selected from branched C1 -20 Alkyl or linear C1 -20 alkyl.

[0011] In some embodiments, R1, R2, R3, R4, and R5 are independently selected from branched C1 -8 Alkyl or linear C1 -8 alkyl.

[0012] In some embodiments, R1, R2, R3, R4, and R5 are independently selected from branched C1 -3 Alkyl or linear C1 -3 alkyl.

[0013] In some embodiments, R1, R2, R3, R4, R5 are independently selected from saturated alkyl groups.

[0014] In some embodiments, R1, R2, R3, R4, and R5 are groups that at least break the bond between the aromatic ring and the carbon group.

[0015] In some preferred embodiments, R1, R2, R3, R4, and R5 are all methyl groups.

[0016] In some embodiments, the compound of formula II is obtained by reacting a compound of formula I with an alkyl lithium or an aryl lithium at a temperature below -40°C.

[0017]

[0018] In some embodiments, the alkyl lithium is, for example, methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, pentyl lithium, hexyl lithium, cyclohexyl lithium, tert-octyl lithium, n-eicosyl lithium, phenyl lithium, methylphenyl lithium, butylphenyl lithium, naphthyl lithium, butylcyclohexyl lithium, and the like.

[0019] In some embodiments, an initiator, an oxidant and an alkaline reagent are used in the step (S1), wherein the initiator includes CuO, triethylborohydride, or at least one of Cu(OTf)2, CuOTf, and FeCl3, the oxidant includes di-tert-butyl peroxide, and the alkaline reagent is an alkali metal phosphate and / or carbonate, preferably the alkaline reagent includes at least one of Cs2CO3, K2CO3 and K2HPO4.

[0020] In some embodiments, the initiator is CuO.

[0021] In some embodiments, the oxidizing agent is tert-butyl hydroperoxide.

[0022] In some embodiments, the base reagent is Cs2CO3.

[0023] In a second aspect of the present invention, a compound is provided, which has a structure of formula IV

[0024]

[0025] Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen or C 1-20 alkyl.

[0026] In a third aspect of the present invention, there is provided a method for preparing a compound of formula V, the method comprising steps (S1) and (S2):

[0027]

[0028] (S1) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV,

[0029] (S2) reacting the compound of formula IV obtained from step (S1) with an electrophilic reagent to obtain a compound of formula V,

[0030] Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen or C 1-20 Alkyl, or at least a group that breaks the bond between the aromatic ring and the carbon group, and wherein R6 is hydrogen.

[0031] In some embodiments, the electrophile is an inorganic acid, and in some embodiments, the inorganic acid comprises at least one of hydrochloric acid and sulfuric acid.

[0032] In some embodiments, the electrophile is Br2, and step (S2) is performed by reacting the compound of formula IV obtained from step (S1) with Br2, followed by reaction with water to obtain the compound of formula V.

[0033] In some embodiments, step (S2) is performed by reacting the compound of formula IV obtained from step (S1) with Br2 and then directly reacting with water without any other treatment to obtain the compound of formula V.

[0034] In a fourth aspect of the present invention, there is provided a method for preparing a compound of formula VI, the method comprising steps (S1) and (S3):

[0035]

[0036]

[0037] (S1) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV;

[0038] (S3) reacting the compound of formula IV obtained from step (S1) with Br2, and then reacting with a nucleophile to obtain a compound of formula VI,

[0039] Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen, alkyl groups that break the aromatic group and the carbonyl group, preferably hydrogen or alkyl groups, and wherein, R6 is hydrogen, Z is selected from -OR, -SR, -NRR', -N3, -NH-OR, wherein R and R' are independently selected from hydrogen, alkyl, aryl, heteroaryl.

[0040] In some embodiments, the nucleophile comprises at least one of HOR, HSR, HNRR', -N3, HN3, NH2-OR, wherein R and R' are independently selected from hydrogen, alkyl, aryl, heteroaryl. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1The schematic diagram shows the possible products of compound C after reacting with Br2 and then reacting with different nucleophiles. DETAILED DESCRIPTION

[0043] The foregoing and other objects, features and advantages will become apparent from the following more detailed description of specific embodiments, as illustrated and exemplified in the accompanying drawings.

[0044] In terms of its scope of use, the terms "including", "comprising" and "having" or any variation thereof as used in the claims and description herein will be considered to indicate an open group that can include unspecified other elements. The terms "one", "a kind of" and the words in the singular form should be understood to include the plural form of the same word, so that these terms represent that one or more things are provided. The terms "at least one" and "one or more" can be used interchangeably. The term "single" is used to indicate one and only one of something. Similarly, when a specific number of things is needed, other specific integer values, such as "two" will be used. The terms "preferably", "preferred", "preferably", "optionally", "can" and similar terms are used to indicate that the quoted items, conditions or steps are optional (that is, not required) features in the embodiment. Unless otherwise stated, the range described as "between a and b" includes the values ​​of "a" and "b".

[0045] Although various improvements have been described herein with reference to specific embodiments of the invention, it should be understood that such description is by way of illustration only and should not be construed as limiting the scope of any claimed invention. Accordingly, the scope and content of any claimed invention will be limited solely by the terms of the appended claims in their current form or as amended during prosecution or in any continuation of application. In addition, it should be understood that, unless otherwise indicated, the features of any specific embodiment discussed herein may be combined with one or more features of any one or more embodiments otherwise discussed or considered herein.

[0046] In the context of the present invention, the term "alkyl" refers to a fully saturated straight or branched hydrocarbon moiety having 1-20 carbon atoms, wherein the alkyl group may be optionally substituted with substituents independently selected from the groups mentioned below. Unless otherwise specified, alkyl refers to a hydrocarbon moiety having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. C 1-3Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl.

[0047] In the context of the present invention, the term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl and anthracenyl). Preferably, the aryl group is a 6 to 10-membered ring system, including phenyl, fluorenyl, naphthyl, anthracenyl, etc. The aryl group may be optionally substituted with 1-5 substituents independently selected from the groups mentioned below.

[0048] In the context of the present invention, unless otherwise stated, the term "optionally substituted" with respect to the groups described herein refers to groups which are unsubstituted or substituted by one or more, e.g. 1 to 5, preferably 1, 2, 3 or 4, suitable non-hydrogen substituents, each of which is independently selected from alkyl, alkenyl, alkynyl, halogen, -oxo (=O), -OX1, -NX1X2, -SX1, nitro, cyano, -COX1, -COOX1, -CONX1X2, cycloalkyl, heterocyclyl, aryl, heteroaryl, as defined herein, wherein X1 and X2 are independently H, saturated straight or branched chain -(C1-C 20 )alkyl, wherein one or two non-adjacent CH2 groups may be replaced by -O-, -CH=CH-, -CO-, -CO-, -COO-, -NCO-, -CON-, in such a way that the O atoms are not directly connected to each other. In the context of the present invention, "nucleophile" is a term understood by those skilled in the art, and "nucleophile" refers to a reagent having nucleophilicity. Examples of nucleophiles include, but are not limited to, uncharged compounds such as alcohols, thiols, alcohols, carboxylic acids, diazo compounds and azides, and charged moieties such as alkoxides, carboxylates, thiols, carbon anions, metallated amines (e.g., amine anions, such as sodium amide) and various organic and inorganic anions (e.g., NaN3). The nucleophiles used in the present invention are preferably aliphatic and aromatic alcohols of formula HOR, thiols of formula HSR, azide-N3, ammonia (H3N), amines of formula HNR1R2, hydrazines of formula H2N-NHR1, hydroxylamines of formula H2N-OR1.

[0049] Example 1

[0050] [1.1.1] Synthesis of Propellane B

[0051] Under N2 protection, MeLi (3.1M, diethoxymethane solution) (10.9ml, 33.8mmol, 3 equivalents) was added dropwise to a dry diethyl ether solution of compound A1,1-dibromo-2,2-bis(chloromethyl)-cyclopropane (5g, 16.8mmol, 1 equivalent) stirred at -45°C. The resulting mixture was stirred at -45°C for 30 minutes, then warmed to 0°C and continued to stir for 2 hours. The reaction mixture was concentrated by vacuum. The condenser was cooled to -78°C to collect the distillate. The obtained compound B was a 0.3-0.5M diethyl ether solution containing a small amount of diethoxymethane, and the yield of [1.1.1] propeller alkane B was 40%-50%.

[0052] Synthesis of Bicyclo[1.1.1]pentan-1-yl(2,3,4,5,6-pentamethylphenyl)methanone C

[0053] Under N2 protection, pentamethylbenzaldehyde (52.2 mg, 0.3 mmol, 1.0 equiv), H2O (75.0 μL) and TBHP (63 μL, 0.60 mmol, 2.0 equiv; 70% aqueous solution) were added to a toluene (1.5 ml) solution of CuO (2.4 mg, 0.03 mmol, 0.1 equiv) and Cs2CO3 (100 mg, 0.3 mmol, 1.0 equiv). Then, a diethyl ether solution of [1.1.1] propeller alkane (1.9 mL, 0.48 M, 0.9 mmol, 3.0 equiv) was added via a syringe. The resulting mixture was stirred at 90°C for 12 hours. After extraction and purification, compound C was obtained with a yield of 70%-90%.

[0054]

[0055] As in Figure 1 As shown in FIG. 1 , compound C can directly continue to react with different reactants after reacting with Br2 to obtain the corresponding products.

[0056] Example 2: Synthesis of Bicyclo[1.1.1]pentane-1-carboxylic acid D

[0057] Method 1:

[0058] To a solution of compound C (50 mg, 0.2 mmol) in dry CH2Cl2 (1 mL) at -17°C was added dry Br2 (21 μL, 0.4 mmol, 2 eq.). The resulting mixture was stirred at -17°C for 20 minutes, H2O (11 μL, 0.6 mmol, 3 eq.) was added, and the reaction mixture was then warmed to room temperature and stirred for 16 hours. The reactant was diluted with ether and washed with saturated Na2SO3 solution and brine. Extraction and concentration were performed to obtain compound D in a yield of 90%-100% (compound D is volatile).

[0059]

[0060] Method 2:

[0061] Concentrated hydrochloric acid (mL) was added to the hexafluoroisopropanol solution containing compound C (). The reaction mixture was then heated to 65°C and refluxed for 16 hours at this temperature. After the mixture was cooled to room temperature, an appropriate amount of water was added to dilute it, and then extracted with ether. After concentration, compound D was obtained with a yield of up to 70%.

[0062]

[0063] Example 3: Synthesis of N-phenylbicyclo[1.1.1]pentane-1-carboxamide E

[0064] To a solution of compound C (48 mg, 0.2 mmol) dried at -17°C in dry CH2Cl2 (1 mL) was added dry Br2 (21 μL, 0.4 mmol, 2 equiv). After stirring at -17°C for 20 minutes, aniline (55 μL, 0.6 mmol, 3 equiv) was added, and the reaction mixture was then warmed to room temperature and stirred for 20 hours. The reactant was diluted with ether and washed with saturated Na2SO3 solution and brine. After extraction and concentration, compound E was obtained with a yield of 70%.

[0065]

[0066] Example 4: Synthesis of N-(bicyclo[1.1.1]pentane-1-yl)bicyclo[1.1.1]pentane-1-carboxamide G

[0067] To a room temperature dried solution of bicyclo[1.1.1]pentane-1-amine hydrochloride (27 mg, 0.22 mmol) in CH2Cl2 (4 ml) was added Et3N (83 μL, 0.6 mmol, 3 eq.). After stirring for 15 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 57.5 mg, 0.3 mmol, 1.5 eq.) and HOBt (40.5 mg, 0.3 mmol, 1.5 eq.) were added, followed by compound D (21 mg, 0.2 mmol, 1 eq.). After extraction and purification, compound G was obtained with a yield of 68%.

[0068]

[0069] Although some exemplary embodiments of the present application have been illustrated and described, the present application is not limited to the disclosed embodiments. On the contrary, those skilled in the art will recognize that some modifications and changes may be made to the described embodiments without departing from the spirit and scope of the present application as described in the appended claims, and these modifications and changes also fall within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula IV, characterized in that The method comprises the steps (S1): (S1) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV, Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen or C 1-20 Alkyl, and wherein R6 is hydrogen.

2. The method according to claim 1, characterized in that R1, R2, R3, R4, and R5 are groups that at least break the bond between the aromatic ring and the carbonyl group, and preferably all of R1, R2, R3, R4, and R5 are methyl groups.

3. The method according to claim 1, characterized in that The compound of formula II is obtained by reacting the compound of formula I with an alkyl lithium or an aryl lithium at a temperature below -40°C.

4. The method according to claim 1, characterized in that: In the step (S1), an initiator, an oxidant and an alkaline agent are used, wherein the initiator includes CuO, triethylborohydride, or at least one of Cu(OTf)2, CuOTf, and FeCl3, the oxidant includes di-tert-butyl peroxide, and the alkaline agent is a phosphate and / or carbonate of an alkali metal, and preferably the alkaline agent includes at least one of Cs2CO3, K2CO3 and K2HPO4.

5. The method according to claim 4, characterized in that The initiator is CuO, the oxidant is tert-butyl hydroperoxide, and the alkaline agent is Cs2CO3.

6. A compound, characterized in that The compound has the structure of Formula IV Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen or C 1-20 alkyl.

7. A method for preparing a compound of formula V, characterized in that The method comprises steps (S1) and (S2): (S1) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV, (S2) reacting the compound of formula IV obtained from step (S1) with an electrophilic reagent to obtain a compound of formula V, Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen or C 1-20 Alkyl, and wherein R6 is hydrogen.

8. The method according to claim 7, characterized in that The electrophilic reagent is an inorganic acid, and preferably the inorganic acid includes at least one of hydrochloric acid and sulfuric acid.

9. The method according to claim 7, characterized in that: The electrophile is Br2, and step (S2) is performed as follows: the compound of formula IV obtained from step (S1) is reacted with Br2 and then with water to obtain the compound of formula V.

10. A method for preparing a compound of formula VI, characterized in that The method comprises steps (S1) and (S3): (S1) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV; (S3) reacting the compound of formula IV obtained from step (S1) with Br2, and then with a nucleophile to obtain a compound of formula VI, Wherein, R1, R2, R3, R4, R5 are independently selected from hydrogen or C 1-20 Alkyl, and wherein R6 is hydrogen, Z is selected from -OR, -SR, -NRR', -N3, -NH-OR, wherein R and R' are independently selected from hydrogen, alkyl, aryl, heteroaryl.

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