Preparation method of bicyclo [3.1. 1] heptane-3-ketone and intermediate of bicyclo [3.1. 1] heptane-3-ketone

Abstract

The invention provides a preparation method and an intermediate of bicyclo [3.1. 1] heptane-3-ketone (a compound shown in a formula I), and particularly relates to a preparation method and an intermediate of the compound shown in the formula I. The total yield of five-step reaction can reach 36%, the reaction operation is simple and convenient, the condition is mild, and the preparation method is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and in particular to a preparation method of bicyclo[3.1.1]heptane-3-one and an intermediate thereof. Background Art

[0002] In recent years, three-dimensional cage-structured molecules have been a hot research topic in organic chemistry and medicinal chemistry. They can serve as aromatic ring isosteres to replace planar aromatic rings in candidate drug structures to improve their physicochemical properties. Prior to this, bioisosteres of meta-substituted benzenes remained challenging. Recently, the team of Professor Kazunori Miyamoto of the University of Tokyo reported a bicyclo[3.1.1]heptane (BCH) skeleton that can be used as a new type of meta-substituted benzene bioisostere. Bicyclo[3.1.1]heptane-3-one is an important structural fragment of bicyclo[3.1.1]heptane molecular building blocks and can be used as an important intermediate in the research and development of a variety of drugs. The PCT patent WO2022083569A1 public text records that bicyclo[3.1.1]heptane-3-one can be used as an intermediate to prepare 2,6-diazaspiro[3.4]octane drug compounds as G12C mutant KRAS protein inhibitors for the treatment of cancer.

[0003]

[0004] The related document Regioselectivity in ring expansion of 1-substituted bicyclo[2.1.1]hexan-2-ones: preferential migration of methylene over bridgehead carbon (Australian Journal of Chemistry (1983), 36(11), 2261-8) reported a method for preparing bicyclo[3.1.1]heptane-3-one: compound C1 was dissolved in water and reacted with sodium nitrite in the presence of acetic acid to obtain a ring-expanded product, bicyclo[3.1.1]heptane-3-one (compound of formula I).

[0005]

[0006] At present, there are almost no reports on the preparation method of bicyclo[3.1.1]heptane-3-one except the above literature, which restricts its further application in the field of drug discovery. Summary of the invention

[0007] In one aspect, the present invention provides a compound of formula IV, which can be further used to prepare a compound of formula I, wherein each R is independently selected from methyl or ethyl.

[0008]

[0009] On the other hand, the present invention also provides a method for preparing the compound of formula VI, characterized in that it comprises the following steps:

[0010]

[0011] wherein each R is independently selected from methyl or ethyl;

[0012] The compound of formula IV reacts with a reducing agent in the presence of a catalyst to generate a compound of formula V;

[0013] The compound of formula V is dissolved in an organic solvent 1 and undergoes an intramolecular condensation reaction in the presence of an alkaline reagent 1 to obtain a compound of formula VI.

[0014] In certain embodiments, the catalyst is selected from palladium on carbon or palladium hydroxide on carbon; and the reducing agent is hydrogen gas.

[0015] In certain embodiments, the alkaline agent 1 is NaH.

[0016] In certain embodiments, the molar ratio of the compound of formula V to the alkaline agent 1 is in the range of 1:1-3.

[0017] In certain embodiments, the organic solvent 1 is toluene, and the amount used is 8 to 15 times the volume of the compound of formula V.

[0018] In certain embodiments, the reaction temperature is 100-130° C., and the reaction time is 10-20 hours.

[0019] On the other hand, the present invention also provides a method for preparing the compound of formula I, characterized in that it comprises the following steps:

[0020]

[0021] wherein each R is independently selected from methyl or ethyl;

[0022] In step 1, the acidic reagent 1 is one of concentrated sulfuric acid, p-toluenesulfonic acid, hydrochloric acid or phosphoric acid; the alcohol is methanol or ethanol; the reaction temperature is 70-80° C.; the reaction time is 3-7 hours;

[0023] In step 2, the alkaline reagent 2 is one or more of potassium tert-butoxide, DBU, NaH, potassium isopropoxide, potassium tert-amyloxide, sodium methoxide or sodium ethoxide; the phosphonoacetate is one of trimethyl phosphonoacetate or triethyl phosphonoacetate; the molar ratio of the compound of formula III to the phosphonoacetate and the alkaline reagent 1 is in the range of 1:1 to 2:1 to 3;

[0024] In step 3, the reducing agent is hydrogen, and the catalyst is selected from palladium carbon or palladium hydroxide on carbon;

[0025] In step 4, the alkaline reagent 1 is NaH; the molar ratio of the compound of formula V to the alkaline reagent 1 is in the range of 1:1 to 3; the organic solvent 1 is toluene, and the amount used is 8 to 15 times the volume of the compound of formula V; the reaction temperature is 100 to 130° C., and the reaction time is 10 to 20 hours;

[0026] In step 5, the chlorine-containing inorganic salt is selected from sodium chloride or lithium chloride; the molar ratio of the compound of formula VI to the chlorine-containing inorganic salt is in the range of 1:1 to 3; DMSO and H 2 The preparation volume ratio of DMSO / H 2 The amount of O used is 8 to 15 times the volume of the compound of formula VI; the reaction temperature is 110 to 160° C.; and the reaction time is 1 to 5 hours.

[0027] In certain embodiments, in step 4, the alkaline reagent 1 is NaH, and the reaction temperature is 110-120°C.

[0028] In certain embodiments, the chlorine-containing inorganic salt in step 5 is sodium chloride; DMSO / H 2 The amount of O used is 10 to 12 times the volume of the compound of formula VI; the reaction temperature is 125 to 130° C.; and the reaction time is 2 to 3 hours.

[0029] The technical solution of the present invention fills the technical gap in the prior art for preparing bicyclo[3.1.1]heptane-3-one (compound of formula I), the total yield of the five-step reaction can reach 36%, the reaction operation is simple, the conditions are mild, and it is suitable for industrial production.

[0030] The abbreviations of some reaction reagents involved in the present invention are as follows:

[0031] MTBE: Methyl tert-butyl ether

[0032] THF: Tetrahydrofuran

[0033] n-hep: normal heptane

[0034] Tol: Toluene

[0035] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present invention.

[0037] Figure 1 The final product of Example 1 of the present invention (compound of formula I) 1 H NMR spectrum. DETAILED DESCRIPTION

[0038] Example 1

[0039] Step 1:

[0040]

[0041] The compound of formula II (50.00 g, 0.39 mol, 1.0 eq.) was dissolved in ethanol (300 mL), and concentrated sulfuric acid (2.67 g, 19.5 mmol, 0.05 eq.) was added. The reaction was carried out at 80°C for 5 h. After GC detection, the reaction was complete, the temperature was lowered to below 50°C, the ethanol was removed by rotation, acetone (200 mL) was added to the residue, and the temperature was heated to 45°C in a water bath, and the reaction was carried out for 1 h. After the acetone was removed by rotation, MTBE (300 mL) was added to the residue, and saturated NaHCO 3 The pH was adjusted to about 7, and the liquids were separated; the organic phase was then washed with saturated brine (100 mL*1), dried over anhydrous magnesium sulfate for 1 h, filtered, and concentrated at 45° C. to obtain 60.00 g of compound III-1 with a yield of 100%.

[0042] Step 2:

[0043]

[0044] Under nitrogen atmosphere, potassium tert-butoxide (47.42 g, 0.42 mol, 1.1 eq.) was added to THF, and the temperature of the reaction system was cooled to below 10°C. Triethyl phosphonoacetate (94.16 g, 0.42 mol, 1.1 eq.) was added dropwise thereto. After the addition was completed, the reaction was carried out for 0.5 h, and a large amount of white solid precipitated. Then, a THF solution (100 mL) of the compound of formula III-1 (60.00 g, 0.38 mol, 1.0 eq.) was added dropwise to the reaction solution. During the addition, the temperature of the reaction system was controlled below 15°C. After the addition was completed, the reaction was carried out for 3 h. GC detected that the reaction was complete, and the reaction solution was carefully poured into ice water (600 mL) in batches, the organic phase was separated, the aqueous phase was extracted with MTBE (200 mL×3), the organic phases were combined and washed with 15% NaCl (250 mL*1), dried, concentrated, sand made, and column chromatography (n-hep:EA=100:1~10:1) to obtain 80.00 g of the product compound of formula IV-1 with a yield of 93%.

[0045] Step 3:

[0046]

[0047] The compound of formula IV-1 (80.00 g, 0.353 mol, 1 eq.) was dissolved in ethanol (500 mL), palladium carbon was added, and the reaction was carried out at room temperature (30° C.) under a hydrogen atmosphere overnight. The raw material reaction was complete by GC detection, and the filter cake was washed with ethanol (100 mL). The combined filtrate was concentrated to dryness, and MTBE (300 mL) was added thereto; anhydrous magnesium sulfate was added, and the mixture was dried for 30 min, filtered, and the filtrate was dried to obtain 80.00 g of the compound of formula V-1, with a yield of 99%.

[0048] Step 4:

[0049]

[0050] Under nitrogen atmosphere, NaH (14.70 g, 0.367 mol, 1.5 eq.) was dissolved in toluene, and the compound of formula V-1 (56.00 g, 0.245 mol, 1 eq.) was added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 110°C and the reaction was refluxed for 15 h. The reaction was complete after GC detection, and the temperature was lowered to 30°C. The reaction solution was added to 1M HCl solution (400 mL) in batches and stirred for 30 min. The aqueous phase was extracted with MTBE (200 mL*2), washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and distilled under reduced pressure with a 45°C oil pump to collect the fraction at 100-102°C to obtain 24.00 g of the compound of formula VI-1 with a yield of 54%.

[0051] Step 5:

[0052]

[0053] The compound of formula VI-1 was dissolved in DMSO / H 2 O mixed solution (200mL / 20mL), add NaCl (10.26g, 175.60mmol, 2eq.) to the reaction system, heat to 125-130℃, and react for 2h. GC detection reaction is complete, cool to 30℃, pour the reaction solution into water (600mL), extract with MTBE (150mL*4), combine MTBE and wash with 15% brine (300mL*5) until no DMSO remains; add anhydrous magnesium sulfate to dry, filter and concentrate to obtain a solid-liquid mixture, add PE (15mL), pulp and filter to obtain 3.50g of white solid. The filtrate is concentrated in a water bath, distilled under reduced pressure, and the 70-80℃ fraction is collected to obtain a total of 7.00g of the compound of formula I with a yield of 72%. 1 HNMR (400MHz, CDCl 3 )δ(ppm)2.58-2.66(m, 6H); 2.34-2.36(m, 2H); 1.38-1.41(m, 2H); LC-MS[M+1] + :111.

[0054] Comparative Example 1

[0055] Referring to the method of Example 1, screening tests were conducted on the reaction conditions of each step. The results are shown in Table 1.

[0056] Table 1 Experimental condition screening for step 4

[0057]

[0058]

[0059] As can be seen from the examples, the preferred reaction conditions of the present application for preparing the above-mentioned bicyclo[3.1.1]heptane-3-one (compound of formula I) and its intermediates have a higher reaction conversion rate, lower production cost, milder reaction conditions, and are suitable for industrial production.

[0060] Although the above describes the specific implementation methods of the present invention, it is not intended to limit the scope of protection of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. Compounds of formula IV: Each R is independently selected from methyl or ethyl.

2. A method for preparing a compound of formula VI, characterized in that The following steps are included: Each R is independently selected from methyl or ethyl; Step 1, the compound of formula IV reacts with a reducing agent in the presence of a catalyst to generate a compound of formula V; Step 2: The compound of formula V is dissolved in an organic solvent 1, and undergoes an intramolecular condensation reaction in the presence of an alkaline reagent 1 to obtain a compound of formula VI.

3. The preparation method according to claim 2, characterized in that: The catalyst is selected from palladium carbon or palladium hydroxide carbon; the reducing agent is hydrogen.

4. The preparation method according to claim 2, characterized in that: The alkaline agent 1 is selected from NaH.

5. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula V to the alkaline reagent 1 is in the range of 1:1-3.

6. The preparation method according to claim 2, characterized in that: The organic solvent 1 is toluene, and the amount used is 8 to 15 times the volume of the compound of formula V.

7. The preparation method according to claim 2, characterized in that: The reaction temperature is 100-130°C, and the reaction time is 10-20 hours.

8. A method for preparing a compound of formula I, characterized in that The following steps are included: wherein each R is independently selected from methyl or ethyl; In step 1, the acidic reagent 1 is one of concentrated sulfuric acid, p-toluenesulfonic acid, hydrochloric acid or phosphoric acid; the alcohol is methanol or ethanol; the reaction temperature is 70-80° C.; the reaction time is 3-7 hours; In step 2, the alkaline reagent 2 is one or more of potassium tert-butoxide, DBU, NaH, potassium isopropoxide, potassium tert-amyloxide, sodium methoxide or sodium ethoxide; the phosphonoacetate is one of trimethyl phosphonoacetate or triethyl phosphonoacetate; the molar ratio of the compound of formula III to the phosphonoacetate and the alkaline reagent 1 is in the range of 1:1 to 2:1 to 3; In step 3, the reducing agent is hydrogen, and the catalyst is selected from palladium carbon or palladium hydroxide on carbon; In step 4, the alkaline reagent 1 is NaH; the molar ratio of the compound of formula V to the alkaline reagent 1 is in the range of 1:1 to 3; the organic solvent 1 is toluene, and the amount used is 8 to 15 times the volume of the compound of formula V; the reaction temperature is 100 to 130° C., and the reaction time is 10 to 20 hours; In step 5, the chlorine-containing inorganic salt is selected from sodium chloride or lithium chloride; the molar ratio of the compound of formula VI to the chlorine-containing inorganic salt is in the range of 1:1 to 3; the preparation volume ratio of DMSO to H2O is 8 to 12:1; the amount of DMSO / H2O is 8 to 15 times the volume of the compound of formula VI; the reaction temperature is 110 to 160°C; and the reaction time is 1 to 5 hours.

9. The preparation method according to claim 8, characterized in that: In step 4, the alkaline reagent 1 is NaH, and the reaction temperature is 110-120°C.

10. The preparation method according to claim 8, characterized in that: In step 5, the chlorine-containing inorganic salt is sodium chloride; the amount of DMSO / H2O used is 10 to 12 times the volume of the compound of formula VI; the reaction temperature is 125 to 130°C; and the reaction time is 2 to 3 hours.

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