CN117466796A - Preparation method of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol - Google Patents

Preparation method of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol Download PDF

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CN117466796A
CN117466796A CN202210864172.8A CN202210864172A CN117466796A CN 117466796 A CN117466796 A CN 117466796A CN 202210864172 A CN202210864172 A CN 202210864172A CN 117466796 A CN117466796 A CN 117466796A
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compound
reaction
sodium
allyl
potassium
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胡益平
王诚
杨成武
李硕梁
陈永刚
高强
郑保富
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Shanghai Haohong Biomedical Technology Co ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention provides a method for preparing a compound I, wherein the reaction formula is as follows:

Description

Preparation method of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol
Technical Field
The invention belongs to the field of pharmaceutical chemistry, relates to preparation of a key intermediate of a compound for inhibiting KRAS G12D or KRAS G12C, and in particular relates to a preparation method of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol.
Background
KRAS gene mutation is one of the most common activating mutations in human cancers, and is present in 90% of pancreatic cancers, 40% of colon cancers, and 20% of lung cancers. The KARS protein is a target point which is extremely difficult to prepare due to the smooth space structure of the KARS protein and the extremely strong affinity of the GTP skin molar level. The glycine (G) mutated to codon 12 of KARS G12D is replaced by aspartic acid (D) ending in a carboxylic acid, and no drug has been marketed for this target, but WO2022105859A1, WO2022098625A1, WO2022015375A1/WO2021041671A1, WO2021139748A1, WO2022002102A1 and WO2022031678A1 patents disclose novel compounds for this target, all containing fragments of formula I below.
KRAS G12C mutation to a mutation in which glycine at position 12 is replaced with cysteine, wherein the target inhibitors disclosed in WO 2020146613A 1, WO2022081655A1, WO2021180181A1 and WO2021259331A1 all also contain a fragment of formula I. WO2021139748 spiro tetrahydroquinazoline KRAS inhibitors also contain this fragment, CN114031562a/CN114057776a discloses inhibitor compounds that selectively inhibit KRAS mutations, also contain a fragment of formula I, protecting two different preparation processes.
CN114615981A (WO 2022015375A1/WO2021041671A 1) discloses the synthetic route as follows:
the overall yield of this route is low, 3.5% only, and involves steps that are difficult to implement in scale-up production, such as ozonation and chiral chromatographic resolution, and thus difficult to industrialize.
WO2022002102A1 discloses the synthetic route as follows:
the patent starts from chiral fluoro raw materials and obtains target products through nine steps, and relates to multiple reduction and Dess-Martin periodate oxidation by different reducing agents, so that the production cost is high, and meanwhile, the yield and selectivity are not mentioned in the reaction route.
In summary, the method reported in the prior art has the problems of complicated steps, harsh reaction conditions, high cost, low yield and the like; therefore, there is still a need to develop a high-efficiency production method of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol, which is simple and convenient to operate, high in safety, low in cost, good in selectivity and high in yield, and is suitable for industrial large-scale production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing the compound shown in the formula I, which is completely different from the prior art, and the method has the advantages of mild reaction conditions, environment friendliness, novel route, simple post-treatment and purification, high purity of the prepared compound shown in the formula I, high yield of the preparation method, low cost, good reaction selectivity and contribution to industrial expansion production; the compound shown in the formula I can be used for preparing a medicine for inhibiting KRAS gene mutation, in particular to an application for preparing a medicine for inhibiting KRAS G12D or KRAS G12C.
In order to solve the problems, the invention also provides a key intermediate compound C (2S, 4R) -1- (3-halopropyl) -4-fluoropyrrolidine-2-carboxylate and a preparation method thereof, and further application thereof in preparing a compound ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol shown in a formula I.
The technical scheme of the invention is as follows:
the invention provides a key intermediate for preparing a compound I. In certain embodiments, the key intermediate is represented by compound C:
wherein: x is Cl, br, I, OTs, OTf or OMs; r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, tert-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl.
As a further improvement of the present invention, the X is preferably Cl, br or I, more preferably Cl or Br; the R is preferably methyl, ethyl, isopropyl, benzyl or tert-butyl, more preferably methyl, ethyl or benzyl, most preferably methyl.
As a further improvement of the present invention, X is Cl and R is methyl.
As a further development of the invention, compound C is selected from, without limitation, the following compounds or any of the groups:
in a preferred embodiment of the present invention, the present invention provides a process for preparing compound C, which further comprises preparing compound C from compound B.
In another aspect of the present invention, there is provided a process for the preparation of compound C, the reaction formula being as follows:
wherein: r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, t-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; x and Y may each be independently selected from Cl, br, I, OTs, OTf or OMs;
comprises the following steps:
the compound B is reacted with the catalyst under the action of acid binding agentAnd carrying out nitrogen alkylation reaction on the disubstituted propane to obtain a compound C.
As a further improvement of the invention, the molar ratio of the compound B to the acid-binding agent is 1:1-10, preferably 1:1-5;
as a further improvement of the invention, the acid-binding agent is an organic base or an inorganic base, 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, sodium bicarbonate, more preferably sodium carbonate or potassium carbonate;
as a further improvement of the invention, the catalyst is potassium iodide, sodium iodide, potassium bromide or sodium bromide, and the molar amount of the catalyst is 0.05-3%, preferably 0.08-1%, more preferably 0.2-0.5% of the molar amount of the compound B;
as a further development of the invention, the nitrogen alkylation reaction is carried out in an organic solvent which 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, most preferably acetone; the use amount of the organic solvent is 1 to 30 times, preferably 2 to 10 times of the weight g of the compound B;
as a further development of the invention, the said compound B reacts withThe molar ratio of the disubstituted propane is 1: (1 to 10), preferably 1: (2-5);
as a further development of the invention, the nitrogen alkylation reaction is from room temperature to reflux temperature, preferably room temperature reaction; the reaction time is 2 to 24 hours, preferably 2 to 10 hours.
In a preferred embodiment of the present invention, the present invention also provides a process for preparing compound B, which further comprises preparing compound B by deprotecting compound a, which is represented by the following formula:
wherein: r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, t-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl;
PG is an amino protecting group, and the amino protecting group is a conventional amino protecting group in organic synthesis. Amino protecting groups include, but are not limited to, t-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-trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc).
As a further development of the 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.
As a further preferred aspect of the present invention, when R in the compound A is methyl and PG is Boc, the compound A is dissolved in a suitable solvent and a deprotecting agent (e.g., CF 3 COOH or hydrochloric acid), and the corresponding compound B is obtained through deprotection reaction.
The conditions for removing the amino protecting group PG are conventional conditions for removing the amino protecting group in organic synthesis.
The invention relates to all the steps involving removal of the protecting groups, the deprotection conditions employed being conventional amino protecting group removal conditions in organic synthesis, suitable protecting groups being deprotected in order to allow synthesis of the compounds according to the inventionCleavable under acid conditions, e.g. Boc or Ts, further preferred deprotecting agents HCl, CF 3 COOH、CCl 3 COOH, perchloric acid, and the like; cleavable under deprotection reagent base conditions, e.g. Fmoc or acetyl; cleavable under reducing conditions, such as Ts; can be removed under hydrogenolysis, such as palladium carbon hydrogen as deprotection agent, palladium carbon hydrogen hydroxide, zinc hydrochloric acid, magnesium methanol, etc., such as Bn or Cbz; the catalyst may be cleavable using a metal catalyst, such as Alloc or Troc.
The amino protecting group and the condition for removing the amino protecting group described in the invention comprise all the amino protecting groups and the condition for removing the amino protecting group described in the description of protecting group (original fifth edition) -protection of amino, alkyne hydrogen and phosphate in organic synthesis, xu Sheng, translation, university of eastern chemical industry, verlag, 1 st edition, and 2016, 1 month.
In yet another aspect of the present invention, there is provided a process for preparing compound I, the reaction formula is as follows:
wherein: r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, t-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; x is selected from Cl, br, I, OTs, OTf or OMs;
comprises the following steps:
in a proper solvent, carrying out ring closure reaction on the compound C under the alkaline condition to obtain a compound D;
and (3) carrying out reduction reaction on the compound D in an organic solvent under the action of a reducing agent to obtain a compound I.
As a further improvement of the present invention, in the ring-closing reaction, the suitable solvent is one or more of methanol, ethanol, isopropanol, t-butanol, toluene, xylene, trimethylbenzene, methylene chloride, 1, 2-dichloroethane, 1, 2-tetrachloroethane, chloroform, DMSO, DMF, tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, acetone or benzene, preferably DMF, methyltetrahydrofuran or tetrahydrofuran.
As a further improvement of the present invention, in the ring closure reaction, the base is sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium isopropylamide, preferably potassium hexamethyldisilazide.
As a further improvement of the present invention, in the ring-closing reaction, the molar ratio of the compound C to the base is 1:1 to 5, preferably 1:1 to 3, more preferably 1:1 to 1.5.
As a further development of the invention, the ring closure reaction is carried out at a temperature of-80 to 0 ℃, preferably-70 to-20 ℃, most preferably-50 to-30 ℃.
As a further preferred aspect of the present invention, the compound D may be selectively isolated and purified; the separation and purification of the compound D is a conventional procedure in the art, including, for example, recrystallization, quenching, solvent extraction, washing, drying, column chromatography, or the like.
As a further improvement of the present invention, in the reduction reaction, the organic solvent is selected from one or any combination of toluene, tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, tert-butyl methyl ether or isopropyl ether, preferably tetrahydrofuran.
As a further development of the invention, the reducing agent in the reduction reaction is selected from lithium aluminum hydride, sodium borohydride, borane, diisobutyl aluminum hydride DIBAL-H or lithium borohydride, preferably lithium aluminum hydride.
In a further preferred aspect of the present invention, the molar ratio of the compound D to the reducing agent in the reduction reaction is 1:1 to 5, preferably 1:1.5 to 3.5.
In a further preferred aspect of the present invention, the reduction reaction is carried out at a temperature of-10 to 70 ℃, preferably-10 to 30 ℃, and most preferably-5 to 20 ℃.
In a further aspect of the invention there is provided the use of the novel compound C described above or of the process for preparing compound I for the preparation of a medicament for inhibiting KRAS gene mutation, in particular for the preparation of a medicament for inhibiting KRAS G12D or KRAS G12C.
Compared with the prior art, the invention also provides a novel key intermediate compound C, a preparation method thereof and a method for further preparing a compound I ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol from the key intermediate compound C, wherein the compound I can be used for preparing a medicament for inhibiting KRAS gene mutation, in particular to the application of preparing a medicament for inhibiting KRASG12D or KRAS G12C; the process for preparing compound I has the advantages that:
1) The preparation method of the compound I comprises the following steps: and (3) starting from the compound A, removing the protecting group on the nitrogen atom to obtain a compound B, and carrying out a nitrogen alkylation reaction on the exposed amino group to obtain a compound C. The subsequent ring closure of the chiral memory (memory of chirality) occurs, stereoselectively yielding compound D, and finally reducing the ester group to yield the desired product compound I.
2) The method screens the starting materials, controls the sequence of deprotection and alkylation reaction, constructs a key intermediate compound C, wherein the compound C is a novel intermediate compound, skillfully performs deprotection reaction and then nitrogen alkylation reaction, controls the molar ratio of the deprotection reaction compound A to the deprotection agent to be in a smaller range, has simple operation, small using amount of organic solvent, mild reaction condition, short time and high yield, and the two-step yield is about 70%.
3) The invention controls the conditions of ring closing and reduction reaction, so that the reaction is simple, the selected reagent is conventional, the safety is high, the cost is low, the selectivity is good, the isomerization reaction is not performed, the invention is suitable for large-scale production, and the reaction yield is high.
4) The invention relates to two ring systems, namely a fluorine chiral center and an aza quaternary carbon chiral center, which have higher synthesis difficulty, but the invention breaks through the difficulty, and has higher yield, high product quality and chiral purity of more than 99.0 percent.
Detailed Description
To facilitate understanding of the present disclosure by those skilled in the art, the technical scheme of the present disclosure will be further described with reference to specific examples, but the following description is not intended to limit the scope and spirit of the present disclosure as claimed in the claims. The raw materials, reagents, or solvents used in the present invention are commercially available without any particular explanation.
The preparation method of the compound I comprises the following steps: starting from the compound A, removing the protecting group on the nitrogen atom to obtain a compound B; then the exposed amino group undergoes a nitrogen alkylation reaction to obtain a compound C; then, a ring closing reaction of chiral memory (memory of chirality) occurs, and a compound D is obtained in a stereoselective manner; finally, the desired product compound I is obtained after the ester group is reduced, the total yield is high, and the chiral purity of the compound I is good.
Example 1: preparation of Compound 3
20g of Compound 2 was dissolved in methylene chloride (400 mL), trifluoroacetic acid (100 mL) was added dropwise under ice bath, and then the mixture was reacted at room temperature for 4 hours, followed by separation, release and concentration to dryness, whereby 11.5g of crude product of Compound 3 was obtained.
Example 2: preparation of Compound 4a
Compound 3 (5.95 g,40.4mmol,1.0 equiv) was dissolved in acetone (50 mL), then 1-bromo-3-chloropropane (31.8 g,202.4mmol,5.0 equiv) potassium carbonate (27.9 g,202.4mmol,5.0 equiv) and potassium iodide (1.3 g,8.08mmol,0.2 equiv) were added, and then the reaction was heated under reflux for 3h. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated and passed through a column to give 6.2g of a colorless oily compound 4a in 69% yield. MS (ESI) m/z calcd for C 9 H 16 ClFNO 2 + ,[M+H] + :224.1,found:224.2. 1 H NMR(400MHz,DMSO-d 6 )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(dd,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-d 6 )δ172.9,92.8(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.
Example 3: preparation of Compound 5
N 2 Compound 4a (2 g,8.9mmol,1.0 equiv) was dissolved in DMF (45 mL) and cooled to-50deg.C, and KHMDS (11.1 mL,11.1mmol,1.25 equiv) solution in tetrahydrofuran was added dropwise thereto and the reaction was maintained at-50deg.C. After 0.5h, the reaction was quenched by adding 10% aqueous ammonium chloride, and after returning to room temperature, extracted with ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After purification by column chromatography, 50.9g of the product compound was obtained as a pale yellow oil with a yield of 54%. 1 H NMR(400MHz,CDCl 3 )δ5.29(dd,J＝4.6,2.9Hz,0.5H),5.15(dd,J＝3.5,2.4Hz,0.5H),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,CDCl 3 )δ-173.14.；MS(ESI):m/z calcd for C 9 H 15 FNO 2 + ,[M+H] + :188.1,found:188.2.
Example 4: preparation of Compound I
Compound 5 (196 mg,1.05mmol,1 eq) was dissolved in THF (2.6 mL) and cooled to 0deg.C, liAlH 4 (119 mg,3.1mmol,3.0 eq) was added and the reaction was maintained at 0deg.C. Half an hour later, water (0.12 mL), 15% NaOH aqueous solution (0.24 mL) and water are added in sequence0.36 mL), filtering with diatomite, washing with ethyl acetate, concentrating the filtrate, and purifying by column chromatography to obtain 164mg of the product compound I as pale yellow solid, wherein the yield is 98%, and the chiral purity is 99.04%. 1 HNMR(400MHz,CDCl 3 )δ5.25(m,0.5H),5.11(m,0.5H),3.35(brs,1H),3.25(s,2H),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),2.06(s,0.5H),2.01(dd,J＝7.1,2.9Hz,1H),1.96–1.82(m,2H),1.82–1.66(m,2H). 13 C NMR(100MHz,CDCl 3 )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,CDCl 3 )δ-172.2.m/z calcd for C 8 H 15 FNO + ,[M+H] + :160.1,found:160.3.

Claims (10)

1. A process for preparing compound C, the reaction formula is as follows:
wherein: r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, t-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; x and Y are each independently selected from Cl, br, I, OTs, OTf or OMs;
comprises the following steps:
the compound B is reacted with the catalyst under the action of acid binding agentAnd carrying out nitrogen alkylation reaction on the disubstituted propane to obtain a compound C.
2. The method according to claim 1, characterized in that: the molar ratio of the compound B to the acid binding agent is 1:1-10, preferably 1:1-5;
the acid-binding agent is organic base or inorganic base, 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, sodium bicarbonate, more preferably sodium carbonate or potassium carbonate;
or preferably the catalyst is potassium iodide, sodium iodide, potassium bromide or sodium bromide, the molar amount of the catalyst is 0.05-3%, preferably 0.08-1%, more preferably 0.2-0.5% of the molar amount of the compound B.
3. The method according to claim 1, characterized in that: the nitrogen alkylation reaction is carried out in an organic solvent which 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, most preferably acetone; the use amount of the organic solvent is 1 to 30 times, preferably 2 to 10 times of the weight g of the compound B;
or a nitrogen alkylation reaction, said compound B being reacted withThe molar ratio of the disubstituted propane is 1: (1 to 10), preferably 1: (2-5);
or 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.
4. A process for preparing compound I, the reaction formula is as follows:
wherein: r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, t-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl; x is selected from Cl, br, I, OTs, OTf or OMs;
comprises the following steps:
in a proper solvent, carrying out ring closure reaction on the compound C under the alkaline condition to obtain a compound D;
and (3) carrying out reduction reaction on the compound D in an organic solvent under the action of a reducing agent to obtain a compound I.
5. The method according to claim 4, wherein: in the ring closure reaction, the suitable solvent is one or more of methanol, ethanol, isopropanol, tertiary butanol, toluene, xylene, trimethylbenzene, methylene dichloride, 1, 2-dichloroethane, 1, 2-tetrachloroethane, chloroform, DMSO, DMF, tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, acetone or benzene, preferably DMF, methyltetrahydrofuran or tetrahydrofuran.
6. The method according to claim 4, wherein: in the ring closure reaction, the alkali is sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or lithium isopropylamide, preferably potassium hexamethyldisilazide;
in the ring closure reaction, the molar ratio of the compound C to the alkali is 1:1-5, preferably 1:1-3, and more preferably 1:1-1.5; in the ring closure reaction, the reaction is carried out at a temperature of-80 to 0 ℃, preferably-70 to-20 ℃, and most preferably-50 to-30 ℃.
7. The method according to claim 4, wherein: in the reduction reaction, the organic solvent is selected from one or any combination of toluene, tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, tertiary butyl methyl ether and isopropyl ether, and preferably tetrahydrofuran;
or in a reduction reaction, the reducing agent is selected from lithium aluminum hydride, sodium borohydride, borane, diisobutyl aluminum hydride DIBAL-H or lithium borohydride, preferably lithium aluminum hydride;
or in the reduction reaction, the mol ratio of the compound D to the reducing agent is 1:1-5, preferably 1:1.5-3.5;
or in the reduction reaction, the reduction reaction is carried out at a temperature of-10 to 70 ℃, preferably-10 to 30 ℃, and most preferably-5 to 20 ℃.
8. The method according to one of claims 4-7, characterized in that: compound D can be selectively isolated and purified; separation and purification are recrystallization, quenching, solvent extraction, washing, drying or column chromatography.
9. An intermediate is prepared from a compound C, and has the following structural formula:
wherein: x is Cl, br, I, OTs, OTf or OMs; r is allyl, alkyl with 1-6 carbon atoms or aryl substituted alkyl; preferably R is allyl, methyl, ethyl, isopropyl, t-butyl, benzyl, p-methylbenzyl, p-nitrobenzyl or p-methoxybenzyl;
preferably compound C is selected from the group consisting of, but not limited to:
10. a method for preparing a medicament for inhibiting KRAS gene mutation, which is characterized by comprising the following steps: comprising a method according to one of claims 1 to 3 or a method according to one of claims 4 to 7 or a compound C according to claim 9.
CN202210864172.8A 2022-07-20 2022-07-20 Preparation method of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methanol Pending CN117466796A (en)

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