A process for the preparation of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol

Abstract

The application provides a method for preparing compound I, and a reaction formula is shown in the following: wherein R is allyl, alkyl with 1-6 carbon atoms or aryl-substituted alkyl; preferably, R is allyl, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methyl benzyl, p-nitro benzyl or p-methoxy benzyl; and X is selected from Cl, Br, I, OTs, OTf or OMs; the method comprises the following steps: performing a ring-closing reaction on compound C under alkaline conditions in a suitable solvent to obtain compound D; and performing a reduction reaction on compound D in an organic solvent under the action of a reducing agent to obtain compound I. According to the application, the ring-closing and reduction reaction conditions are controlled, so that the reaction is simple, the reagent is conventional, the safety is high, the cost is low, the selectivity is good, there is no isomerization reaction, the reaction is suitable for large-scale production, and the reaction yield is high.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to the preparation of a key intermediate of a compound that inhibits KRAS G12D or KRAS G12C, specifically a method for preparing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol. Background Technology

[0002] KRAS gene mutations are among the most common activating mutations in human cancers, present in 90% of pancreatic cancers, 40% of colon cancers, and 20% of lung cancers. Due to the smooth, spherical spatial structure of the KARS protein and its extremely strong affinity for GTP at the picomolar level, it is a highly difficult target for drug development. The KARS G12D mutation involves the substitution of the glycine (G) at codon 12 with an aspartic acid (D) terminus. Currently, there are no marketed drugs targeting this site. However, patents WO2022105859A1, WO2022098625A1, WO2022015375A1 / WO2021041671A1, WO2021139748A1, WO2022002102A1, and WO2022031678A1 disclose novel compounds targeting this site, all containing the fragment of formula I.

[0003]

[0004] The KRAS G12C mutation is a mutation in which glycine at position 12 is replaced by cysteine. Inhibitors targeting this target disclosed in WO2020146613 A1, WO2022081655A1, WO2021180181A1, and WO2021259331A1 all contain the Formula I fragment. The spirocyclic tetrahydroquinazoline KRAS inhibitor WO2021139748 also contains this fragment. CN114031562A / CN114057776A discloses inhibitory compounds that selectively inhibit KRAS mutations, also containing the Formula I fragment, and protects two different preparation processes.

[0005] The publicly disclosed synthetic route for CN114615981A (WO2022015375A1 / WO2021041671A1) is shown below:

[0006]

[0007] The overall yield of this route is low, at only 3.5%, and it involves steps such as ozonolysis and chiral chromatographic separation, which are difficult to implement in scale-up production, thus making it difficult to industrialize.

[0008] The publicly available synthesis route for WO2022002102A1 is shown below:

[0009]

[0010] This patent describes a process that starts with chiral fluorinated raw materials and proceeds through nine steps to obtain the target product. It involves multiple reductions with different reducing agents and oxidation with Dess-Martin periodate, resulting in high production costs. Furthermore, the reaction route does not mention the yield or selectivity.

[0011] In summary, existing methods suffer from numerous problems, including cumbersome procedures, demanding reaction conditions, high costs, and low yields. Therefore, there is still a need to develop a simple, safe, low-cost, highly selective, and efficient method for the industrial-scale production of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol. Summary of the Invention

[0012] The technical problem to be solved by this invention is to provide a method for preparing the compound shown in Formula I that is completely different from the prior art. The reaction conditions involved are mild and environmentally friendly, the route is novel, and the post-processing and purification are simple. The compound shown in Formula I obtained has good purity, high yield, low cost, good reaction selectivity, and is conducive to industrial-scale production. The compound shown in Formula I can be used in the preparation of drugs that inhibit KRAS gene mutations, especially in the preparation of compound drugs that inhibit KRAS G12D or KRASG12C.

[0013] To address the aforementioned issues, this invention also provides a key intermediate compound C(2S,4R)-1-(3-halopropyl)-4-fluoropyrrolidine-2-carboxylic acid ester and its preparation method, as well as its further application to prepare the compound ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol as shown in Formula I.

[0014] The technical solution of the present invention is as follows:

[0015] This invention provides a key intermediate for the preparation of compound I. In some embodiments, the key intermediate is represented by compound C:

[0016]

[0017] Wherein: X is Cl, Br, I, OTs, OTf or OMs; R is allyl, 1-6 carbon atom alkyl or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl.

[0018] As a further improvement of the present invention, X is preferably Cl, Br or I, more preferably Cl or Br; R is preferably methyl, ethyl, isopropyl, benzyl or tert-butyl, more preferably methyl, ethyl or benzyl, and most preferably methyl.

[0019] As a further improvement of the present invention, X is Cl and R is methyl.

[0020] As a further improvement of the present invention, compound C is not limited to being selected from the group consisting of the following compounds:

[0021]

[0022] In a preferred embodiment of the present invention, the present invention provides a method for preparing compound C, characterized in that the method further includes preparing compound C from compound B.

[0023] In another aspect of the present invention, a method for preparing compound C is provided, wherein the reaction formula is shown below:

[0024]

[0025] Wherein: R is allyl, 1-6 carbon atom alkyl or aryl-substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; X and Y can be independently selected from Cl, Br, I, OTs, OTf or OMs respectively;

[0026] It includes the following steps:

[0027] Compound B was reacted with an acid-binding agent and a catalyst. Disubstituted propane undergoes a nitrogen alkylation reaction to yield compound C.

[0028] As a further improvement of the present invention, the molar ratio of compound B to the acid-binding agent is 1:1 to 10, preferably 1:1 to 5;

[0029] As a further improvement of the present invention, the acid-binding agent is an organic base or an inorganic base, wherein the inorganic base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, calcium oxide, or calcium carbonate, and the organic base is triethylamine, pyridine, diisopropylethylamine, or N,N-dimethylaniline; preferably cesium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate, more preferably sodium carbonate or potassium carbonate;

[0030] As a further improvement of the present invention, the catalyst is potassium iodide, sodium iodide, potassium bromide or sodium bromide, and the molar amount of the catalyst is 0.05% to 3% of the molar amount of compound B, preferably 0.08% to 1%, more preferably 0.2% to 0.5%.

[0031] As a further improvement of the present invention, the nitrogen alkylation reaction is carried out in an organic solvent, wherein the organic solvent is dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, toluene, xylene, chlorobenzene or ethyl acetate, preferably 1,2-dichloroethane, toluene, tetrahydrofuran or acetone, and most preferably acetone; the amount of organic solvent used (mL) is 1 to 30 times the weight (g) of compound B, preferably 2 to 10 times;

[0032] As a further improvement to the present invention, in the nitrogen alkylation reaction, the compound B and... The molar ratio of disubstituted propane is 1:(1-10), preferably 1:(2-5);

[0033] As a further improvement of the present invention, the nitrogen alkylation reaction is carried out at room temperature to reflux temperature, preferably at room temperature; the reaction time is 2 to 24 hours, preferably 2 to 10 hours.

[0034] In a preferred embodiment of the present invention, the present invention also provides a method for preparing compound B, characterized in that the method further includes preparing compound B by a deprotection reaction of compound A, as shown in the following reaction formula:

[0035]

[0036] Wherein: R is allyl, 1-6 carbon atom alkyl or aryl-substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl;

[0037] The PG mentioned in this invention is an amino protecting group. "Amino protecting group" refers to a conventional amino protecting group used in organic synthesis. Amino protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc), benzyl, acetyl, p-toluenesulfonyl (Ts), triphenylmethyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), p-methoxybenzyl (PMB), p-nitrobenzyl (PNB), methoxycarbonyl, ethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), and allyloxycarbonyl (Alloc).

[0038] As a further improvement of the present invention, the deprotection reaction is carried out in a suitable solvent, which is one or any combination of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, toluene or ethyl acetate, preferably dichloromethane, 1,2-dichloroethane or toluene.

[0039] As a further preferred embodiment of the present invention, when R in compound A is methyl and PG is Boc, compound A is dissolved in a suitable solvent, and under ice bath conditions, a deprotecting agent (e.g., CF3COOH or hydrochloric acid) is added to conduct a deprotection reaction to obtain the corresponding compound B.

[0040] The conditions for removing the amino protecting group PG are the same as those for removing amino protecting groups in organic synthesis.

[0041] All steps involving the removal of protecting groups in this invention employ conventional amino protecting group removal conditions used in organic synthesis. To allow the synthesis of compounds according to this invention, suitable protecting groups can be cleaved under acidic conditions with a deprotecting agent, such as Boc or Ts, with HCl, CF3COOH, CCl3COOH, perchloric acid, etc., being more preferably deprotecting agents; can be cleaved under alkaline conditions with a deprotecting agent, such as Fmoc or acetyl; can be cleaved under reducing conditions, such as Ts; can be removed by hydrogenolysis, for example with palladium carbon hydrogen, palladium carbon hydrogen hydroxide, zinc hydrochloric acid, magnesium methanol, etc., such as Bn or Cbz; and can be cleaved using a metal catalyst, such as Alloc or Troc.

[0042] The amino protecting groups and amino protecting group removal conditions described in this invention include all amino protecting groups and amino protecting group removal conditions recorded in the book "Protecting Groups in Organic Synthesis (5th Edition) - Protection of Amino, Alkyne Hydrogen, and Phosphate Esters", translated by Xu Sheng, East China University of Science and Technology Press, 1st edition, January 2016.

[0043] In another aspect of the present invention, a method for preparing compound I is provided, wherein the reaction formula is shown below:

[0044]

[0045] Wherein: R is allyl, 1-6 carbon atom alkyl or aryl-substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; X is selected from Cl, Br, I, OTs, OTf or OMs;

[0046] It includes the following steps:

[0047] In a suitable solvent, compound C undergoes a ring-closure reaction under alkaline conditions to give compound D;

[0048] Compound D was reduced in an organic solvent under the action of a reducing agent to obtain compound I.

[0049] As a further improvement of the present invention, in the ring-closing reaction, the suitable solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, DMSO, DMF, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, or benzene, preferably DMF, methyltetrahydrofuran, or tetrahydrofuran.

[0050] As a further improvement of the present invention, in the ring-closing reaction, the base is sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, or lithium isopropylamide, preferably potassium hexamethyldisilamide.

[0051] As a further improvement of the present invention, in the ring-closing reaction, the molar ratio of compound C to base is 1:1 to 5, preferably 1:1 to 3, and more preferably 1:1 to 1.5.

[0052] As a further improvement of the present invention, the ring-closing reaction is carried out at a temperature of -80 to 0°C, preferably -70 to -20°C, and most preferably -50 to -30°C.

[0053] As a further preferred embodiment of the present invention, the compound D can be selectively separated and purified; the separation and purification of compound D is a conventional operation in the art, including recrystallization, quenching, solvent extraction, washing, drying or column chromatography, etc.

[0054] As a further improvement of the present invention, in the reduction reaction, the organic solvent is selected from toluene, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, diethyl ether, tert-butylmethyl ether or isopropyl ether or any combination thereof, preferably tetrahydrofuran.

[0055] As a further improvement of the present invention, in the reduction reaction, the reducing agent is selected from lithium aluminum hydride, sodium borohydride, borane, diisobutylaluminum hydride (DIBAL-H), or lithium borohydride, preferably lithium aluminum hydride.

[0056] As a further preferred embodiment of the present invention, in the reduction reaction, the molar ratio of compound D to reducing agent is 1:1 to 5, preferably 1:1.5 to 3.5.

[0057] As a further preferred embodiment of the present invention, the reduction reaction is carried out at a temperature of -10 to 70°C, preferably -10 to 30°C, and most preferably -5 to 20°C.

[0058] In another aspect of the invention, a method for preparing compound I using the above-described novel compound C or said compound C is provided for use in the preparation of drugs that inhibit KRAS gene mutations, particularly for the preparation of compound drugs that inhibit KRAS G12D or KRASG12C.

[0059] Compared with the prior art, the present invention also provides a new key intermediate compound C and its preparation method, as well as a method for further preparing compound I ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol from the key intermediate compound C. Compound I can be used in the preparation of drugs that inhibit KRAS gene mutations, especially for the preparation of compound drugs that inhibit KRAS G12D or KRAS G12C. The advantages of the method for preparing compound I are:

[0060] 1) The method for preparing compound I according to the present invention includes the following steps: starting from compound A, removing the protecting group on the nitrogen atom to obtain compound B, then reacting the exposed amino group with nitrogen alkylation to obtain compound C. Next, a chiral memory cyclization reaction occurs, stereoselectively yielding compound D, and finally reducing the ester group to obtain the desired product compound I.

[0061] 2) This invention screens the starting materials, controls the order of deprotection and alkylation reactions, and constructs the key intermediate compound C. Compound C is a novel intermediate compound. This invention ingeniously performs the deprotection reaction first and then the nitrogen alkylation reaction, and controls the molar ratio of the deprotection reaction compound A to the deprotection agent within a small range. The operation is simple, the amount of organic solvent used is small, the reaction conditions are mild, the time is short, and the yield is high. The two-step yield is about 70%.

[0062] 3) By controlling the cyclization and reduction reaction conditions, this invention simplifies the reaction, uses conventional reagents, ensures high safety, low cost, good selectivity, avoids isomerization reactions, is suitable for large-scale production, and achieves high reaction yield.

[0063] 4) This invention relates to two ring systems, a fluorine chiral center and a nitrogen-atomized quaternary carbon chiral center, which is difficult to synthesize. However, this invention overcomes the difficulties and achieves high yield, high product quality, and chiral purity of over 99.0%. Detailed Implementation

[0064] To facilitate understanding of the present invention by those skilled in the art, the technical solution of the present invention will be further described below with reference to specific embodiments. However, the following content is not intended to limit the scope and spirit of the claims. Unless otherwise specified, all raw materials, reagents, or solvents used in the present invention are commercially available.

[0065] The preparation method of compound I of the present invention includes the following steps: starting from compound A, removing the protecting group on the nitrogen atom to obtain compound B; then the exposed amino group undergoes a nitrogen alkylation reaction to obtain compound C; next, a chiral memory cyclization reaction occurs, stereoselectively obtaining compound D; finally, the ester group is reduced to obtain the desired product compound I, with high overall yield and good chiral purity of compound I.

[0066] Example 1: Preparation of compound B1

[0067]

[0068] 20g of compound A1 was dissolved in dichloromethane (400mL), and trifluoroacetic acid (100mL) was added dropwise under ice bath conditions. The mixture was then reacted at room temperature for 4 hours. After separation, freeing, and concentration to dryness, 11.5g of crude product B1 was obtained.

[0069] Example 2: Preparation of compound C1

[0070]

[0071] Compound B1 (5.95 g, 40.4 mmol, 1.0 equiv) was dissolved in acetone (50 mL), followed by the addition of 1-bromo-3-chloropropane (31.8 g, 202.4 mmol, 5.0 equiv), potassium carbonate (27.9 g, 202.4 mmol, 5.0 equiv), and potassium iodide (1.3 g, 8.08 mmol, 0.2 equiv). The mixture was then heated under reflux for 3 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated and column filtered to give 6.2 g of the product, a colorless oily compound C1, in 69% yield. MS (ESI): m / z calcd for C9H 16 ClFNO2 + [M+H] + :224.1,found:224.2. 1H NMR (400MHz, DMSO-d6) δ5.32(t,J=5.1Hz,0.5H),5.18(t,J=5.1Hz,0.5H),3.66(dd,J=9. 8,4.0Hz,2H),3.63(s,3H),3.55(t,J=7.5Hz,1H),3.34(dd,J=11.8,4.8Hz,0.5H),3.26(d d,J=11.8,4.8Hz,0.5H),2.82–2.73(m,1.5H),2.72–2.66(m,0.5H),2.65–2.54(m,1H),2 .31–2.22(m,0.5H),2.20(dd,J=8.0,5.7Hz,1H),2.17–2.06(m,0.5H),1.89–1.77(m,2H); 13 C NMR (100MHz, DMSO-d6) δ 172.9, 92.8 (d, J = 173.4Hz), 63.6, 58.7 (d, J = 22.0Hz), 51.5, 50.5, 43.2, 36.8 (d, J = 22.1Hz), 31.1.

[0072] Example 3: Preparation of compound D1

[0073]

[0074] Under N2 protection, compound C1 (2 g, 8.9 mmol, 1.0 equiv) was dissolved in DMF (45 mL), cooled to -50 °C, and a tetrahydrofuran solution of KHMDS (11.1 mL, 11.1 mmol, 1.25 equiv) was added dropwise, maintaining the reaction at -50 °C. After 0.5 h, the reaction was quenched with 10% ammonium chloride aqueous solution. After returning to room temperature, the mixture was extracted with ethyl acetate, washed three times with water, washed once with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Column chromatography purification yielded 0.9 g of compound D1 as a pale yellow oil, with a yield of 54%. 1H NMR (400MHz, CDCl3) δ5.29 (dd, J=4.6, 2.9Hz, 0.5H), 5.15 (dd, J=3.5, 2.4Hz, 0.5 H),3.70(s,3H),3.39–3.30(m,1H),3.25(dd,J=19.4,2.4Hz,1H),3.20–3.15(m, 1H),2.93(td,J=9.3,6.1Hz,1H),2.52(dd,J=15.1,4.7Hz,0.5H),2.48–2.42(m, 1H), 2.41 (d, J=4.7Hz, 0.5H), 2.24 (dd, J=22.6, 15.1Hz, 1H), 1.97–1.86 (m, 3H).; 19 F NMR (376MHz, CDCl3) δ-173.14.; MS (ESI): m / z calcd for C9H 15 FNO2 + [M+H] + :188.1,found:188.2.

[0075] Example 4: Preparation of Compound I

[0076]

[0077] Compound D1 (196 mg, 1.05 mmol, 1 eq) was dissolved in THF (2.6 mL), cooled to 0 °C, and LiAlH4 (119 mg, 3.1 mmol, 3.0 eq) was added, maintaining the reaction at 0 °C. After half an hour, the reaction was quenched by adding water (0.12 mL), 15% NaOH aqueous solution (0.24 mL), and water (0.36 mL) sequentially. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography to give product compound I 164 mg, a pale yellow solid, with a yield of 98% and a chiral purity of 99.04%. 1 H NMR(400MHz, CDCl3)δ5.25(m,0.5H),5.11(m,0.5H),3.35(brs,1H),3.25(s,2 H),3.21–3.14(m,1H),3.14–3.09(m,1H),3.07(s,0.5H),3.00(dd,J=13.9,3. 1Hz,0.5H),2.90(dd,J=15.0,8.7Hz,1H),2.13(dd,J=14.7,4.5Hz,0.5H),2.0 6(s,0.5H),2.01(dd,J=7.1,2.9Hz,1H),1.96–1.82(m,2H),1.82–1.66(m,2H). 13C NMR(100MHz,CDCl3)δ97.9(d,J=175.2Hz),74.6,68.0,61.2(d,J=19.5Hz),57.1,41.4(d,J=20.0Hz),35.5,25.7. 19 F NMR(376MHz,CDCl3)δ-172.2.m / z calcd for C8H 15 FNO + ,[M+H] + :160.1,found:160.3。

Claims

1. A method for preparing compound C, wherein the reaction formula is shown below: Compound B Compound C in: R is allyl, alkyl or benzyl (1-6 carbon atoms), p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; X and Y are independently selected from Cl, Br, I, OTs, OTf or OMs, respectively. It includes the following steps: Compound B was reacted with an acid-binding agent and a catalyst. Disubstituted propane undergoes a nitrogen alkylation reaction to yield compound C; The acid-binding agent is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, calcium oxide, calcium carbonate, triethylamine, pyridine, diisopropylethylamine, or N,N-dimethylaniline; The catalyst is potassium iodide, sodium iodide, potassium bromide, or sodium bromide.

2. The method according to claim 1, characterized in that: The nitrogen alkylation reaction is carried out in which the molar ratio of compound B to the acid-binding agent is 1:1 to 10. Alternatively, the catalyst may be potassium iodide, sodium iodide, potassium bromide, or sodium bromide, and the molar amount of the catalyst may be 0.05% to 3% of the molar amount of compound B.

3. The method according to claim 2, characterized in that: The nitrogen alkylation reaction is carried out in which the molar ratio of compound B to the acid-binding agent is 1:1 to 5. Alternatively, the molar amount of the catalyst may be 0.08 to 1% of the molar amount of compound B.

4. The method according to claim 3, characterized in that: The catalyst is used in a nitrogen alkylation reaction at a molar amount of 0.2 to 0.5% of the molar amount of compound B.

5. The method according to claim 1, characterized in that: The nitrogen alkylation reaction is carried out in an organic solvent, such as dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, toluene, xylene, chlorobenzene, or ethyl acetate.

6. The method according to claim 5, characterized in that: The organic solvent is 1,2-dichloroethane, toluene, tetrahydrofuran, or acetone; the amount of organic solvent used (mL) is 1 to 30 times the weight (g) of compound B.

7. The method according to claim 6, characterized in that: The amount of organic solvent used (mL) is 2 to 10 times the weight (g) of compound B.

8. The method according to claim 1, characterized in that: Nitroalkylation reaction, wherein compound B and The molar ratio of disubstituted propane is 1:(1-10). Alternatively, the alkylation reaction can be carried out at room temperature to reflux temperature; the reaction time is 2 to 24 hours.

9. The method according to claim 8, characterized in that: The compound B and The molar ratio of disubstituted propane is 1:(2-5); Alternatively, the nitrogen alkylation reaction can be carried out at room temperature; the reaction time is 2 to 10 hours.

10. A method for preparing compound I, wherein the reaction formula is shown below: in: R is allyl, alkyl or benzyl (1-6 carbon atoms), p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; X is selected from Cl, Br, I, OTs, OTf or OMs; It includes the following steps: In a suitable solvent, compound C undergoes a ring-closure reaction under alkaline conditions to give compound D; Compound D undergoes a reduction reaction in an organic solvent under the action of a reducing agent to yield compound I.

11. The method according to claim 10, characterized in that: R is allyl, methyl, ethyl, isopropyl, or tert-butyl.

12. The method according to claim 10, characterized in that: In the ring-closing reaction, the suitable solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, DMSO, DMF, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, or benzene.

13. The method according to claim 10, characterized in that: In the ring-closing reaction, the base is sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, or lithium isopropylamide. In the ring-closing reaction, the molar ratio of compound C to the base is 1:1 to 5; The ring-closing reaction is carried out at a temperature of -80 to 0°C.

14. The method according to claim 13, characterized in that: In the ring-closing reaction, the base is hexamethyldisilamide potassium; In the ring-closing reaction, the molar ratio of compound C to the base is 1:1 to 3; The ring-closing reaction is carried out at a temperature of -70 to -20°C.

15. The method according to claim 14, characterized in that: The ring-closing reaction is carried out at a temperature of -50 to -30°C.

16. The method according to claim 10, characterized in that: In the reduction reaction, the organic solvent is selected from toluene, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, diethyl ether, tert-butyl methyl ether or isopropyl ether, or any combination thereof; In the reduction reaction, the reducing agent is selected from lithium aluminum hydride, sodium borohydride, borane, diisobutylaluminum hydride (DIBAL-H), or lithium borohydride. In the reduction reaction, the molar ratio of compound D to the reducing agent is 1:1 to 5; In the reduction reaction, the reduction reaction is carried out at a temperature of -10 to 70°C.

17. The method according to claim 16, characterized in that: In the reduction reaction, the organic solvent is tetrahydrofuran; In the reduction reaction, the reducing agent is lithium aluminum hydride; In the reduction reaction, the molar ratio of compound D to the reducing agent is 1:1.5 to 3.5; In the reduction reaction, the reduction reaction is carried out at a temperature of -10 to 30°C.

18. The method according to claim 17, characterized in that: In the reduction reaction, the reduction reaction is carried out at a temperature of -5 to 20°C.

19. The method according to any one of claims 10-18, characterized in that: Compound D is selectively isolated and purified; the isolation and purification methods include recrystallization, quenching, solvent extraction, washing, drying, or column chromatography.

20. An intermediate compound C has the following structural formula: in: X is Cl, Br, I, OTs, OTf, or OMs; R is allyl, 1-6 carbon atom alkyl or benzyl, p-methylbenzyl, p-nitrobenzyl, or p-methoxybenzyl.

21. Compound C according to claim 20, characterized in that: R is allyl, methyl, ethyl, isopropyl, or tert-butyl.

22. Compound C according to claim 20, characterized in that: Compound C is selected from the following compounds: 、 、 、 、 、 、 。 23. A method for preparing a drug that inhibits KRAS gene mutations, characterized in that: Includes the method according to any one of claims 1-9, or the method according to any one of claims 10-19, or the use of compound C according to claim 20.

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