CN108863991B - Preparation method and application of 2-hydroxymethyl oxetane derivative - Google Patents
Preparation method and application of 2-hydroxymethyl oxetane derivative Download PDFInfo
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Abstract
The invention discloses a preparation method and application of a 2-hydroxymethyl oxetane derivative, which comprises the following steps: taking the compound II and the compound III as raw materials, and carrying out Barbier reaction to obtain a compound IV; obtaining a compound V after the olefinic bond in the compound IV becomes epoxy; ring opening under alkaline condition to generate compound VI; obtaining a compound VII after ring closure reaction, and finally removing a benzyl protecting group to obtain the 2-hydroxymethyl oxetane derivative (compound I).
Description
Technical Field
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method and application of a 2-hydroxymethyl oxetane derivative.
Background
The oxetane compound is an important medical intermediate, plays an important role in drug development by virtue of a unique structure, and can keep or reduce the lipophilicity of a drug molecule while increasing the metabolic stability of the drug molecule by virtue of a unique cyclic rigid structure. The 2-hydroxymethyl oxetane derivative is one of oxetane compounds, is an important intermediate for medical synthesis, and can be used as a small molecular fragment for preparing a pyrrolopyridine derivative used as an HIV inhibitor; can be used for treating drug-regulated protein kinase and anti-proliferative diseases; can also be used for synthesizing drugs such as gamma-secretase inhibitors and the like, thereby having wide market prospect.
The synthesis of compound I-1 is reported in patent KR 102015141275:
reagents and conditions: (a) acetone, Cu, SnCl2Water, room temperature, 18 h; (b) m-CPBA, DCM, 0-room temperature, 18h, the two-step yield is 52.5%; (c) bu3SnOMe, room temperature-120 ℃, 3 h; (d) the yield is 65 percent at 200 ℃ for 18 h.
The method reports the reaction of allyl bromide (compound II-1) with acetone to form compound IV-1; obtaining a compound V-1 after double bonds generate epoxy through peroxide oxidation; then reacting with tri-n-butylmethoxy tin at high temperature to generate 2-hydroxymethyl-4, 4-dimethyl oxetane (compound I). The tri-n-butyl methoxy tin is used in the third step of the route, the catalyst is expensive, the post-treatment is troublesome, and three wastes are high; and the final step requires high-temperature heating reaction at 200 ℃, so the requirement on equipment is high, and the method is not economical and environment-friendly and is not suitable for industrial production due to comprehensive consideration.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defects of the prior art, and provides a novel method which can avoid using tri-n-butyl methoxy tin. The raw materials are cheap and easy to obtain, and the reaction conditions are much milder than those of the existing route. Thereby reducing the production cost, more importantly, the safety, and being suitable for mass production.
Taking the compound II and the compound III as raw materials, and carrying out Barbier reaction to obtain a compound IV; obtaining a compound V after the olefinic bond in the compound IV becomes epoxy; ring opening under alkaline condition to generate compound VI; obtaining a compound VII after ring closure reaction, and finally removing a benzyl protecting group to obtain the 2-hydroxymethyl oxetane derivative (compound I).
The invention provides a preparation method of a synthetic compound I, which comprises the following steps:
wherein: : r1、R2、R3Are respectively and independently selected from hydrogen, C1-C5 straight-chain alkyl, phenyl, substituted phenyl or R2And R3Saturated cycloalkyl of C4-C7 or substituted saturated cycloalkyl of C4-C7; wherein R is1、R2、R3At least one is hydrogen; the substituent of the substituted phenyl is a C1-C5 straight-chain alkyl; the substituent of the substituted saturated naphthenic base is a C1-C5 straight-chain alkyl; x is chlorine or bromine.
In the step of preparing the compound VI from the compound II and the compound III, Lewis acid can be added in the reaction; the Lewis acid is ammonium chloride, sodium acetate or aluminum chloride.
In the step of preparing the compound IV from the compound II and the compound III, the metal is copper, magnesium, aluminum, tin and zinc; the molar ratio of the compound II to the compound III to the metal is 1: 1-3; the reaction temperature is in the range of-10 to 50 ℃.
In the step of preparing compound V from compound IV, the peroxide is: m-chloroperoxybenzoic acid, t-butyl peroxide, cumene hydroperoxide, urea peroxide, or hydrogen peroxide; the molar ratio of the compound IV to the peroxide is 1: 1-1: 3; the reaction temperature is in the range of-10 to 40 ℃.
In the step of preparing compound VI from compound V, the base is: sodium hydride, potassium hydride, calcium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, or potassium bis (trimethylsilyl) amide. The molar ratio of the compound V to the alkali is 1: 1-1: 5; the reaction temperature range is-78-60 ℃.
In the step of preparing compound VII from compound VI, the base is: sodium hydride, potassium hydride, calcium hydride, lithium diisopropylamide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium tert-butoxide, or sodium tert-butoxide; the sulfonyl chloride/sulfonic anhydride is as follows: p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or p-nitrobenzenesulfonyl chloride; the molar ratio of the compound V, the alkali and the sulfonyl chloride/sulfonic anhydride is 1: 1-3: 1-2; the reaction temperature range is 0-60 ℃.
In the step of preparing the compound I from the compound VII, the catalyst is palladium carbon or palladium hydroxide carbon; the reducing agent is hydrogen, formic acid or ammonium formate; the reaction temperature is in the range of-10 to 60 ℃.
Advantageous effects
Taking the compound II and the compound III as raw materials, and carrying out Barbier reaction to obtain a compound IV; obtaining a compound V after the olefinic bond in the compound IV becomes epoxy; ring opening under alkaline condition to generate compound VI; obtaining a compound VII after ring closure reaction, and finally removing a benzyl protecting group to obtain the 2-hydroxymethyl oxetane derivative (compound I). According to the technical scheme, the ring expansion reaction of the compound VII prepared from the compound V is improved on the basis of the prior art, the yield can reach 75.3%, the expensive catalyst of tri-n-butylmethoxy tin is not needed, the reaction condition is mild, the operation is simple and convenient, and the method is suitable for large-scale production.
Compound XI is disclosed in patent KR1020150141275, compound I-5 can be used to prepare compound XI:
the following synthetic route can be used:
compound XI is a pyrrolopyridine derivative useful as an HIV inhibitor.
Abbreviations for the reagents referred to in the specification are as follows:
NaHMDS: sodium bis (trimethylsilyl) amide;
LiHMDS: lithium bis (trimethylsilyl) amide;
MTBE: methyl tert-butyl ether;
m-CPBA: m-chloroperoxybenzoic acid;
PE: petroleum ether;
THF: tetrahydrofuran;
DCM: dichloromethane;
MeOH: methanol;
EtOH: ethanol;
EA: ethyl acetate;
TsCl: p-toluenesulfonyl chloride;
MsCl: methanesulfonyl chloride.
Detailed Description
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of Compound IV-1
Compound II-1(400g, 3.30mol, 1.0e.q.), compound III-1(480g, 8.26mol, 2.5e.q.) were dissolved in 1.5L of ammonium chloride (320g) aqueous solution, Zn powder (216.2g, 3.30mol, 1.0e.q.) was added in portions, and T was controlled<Stirring at 50 deg.C and 15 deg.C for 3 hr, filtering, washing filter cake with MTBE, extracting with aqueous MTBE, and collecting organic substanceThe combined phases were washed with 1L of saturated brine, dried and concentrated to give 160.0g of Compound IV-1 as a pale yellow liquid with a yield of 48.3%.1H-NMR(400MHz，CDCl3)(ppm)1.24(s，6H)，2.24-2.26(d，2H)，5.11-5.18(m，2H)，5.86-5.93(m，1H)。
Preparation of Compound V-1
Compound IV-1(160.0g, 1.59mol, 1.0e.q.) was dissolved in 2L of DCM and m-CPBA (389.8g, 1.92mol, 1.2e.q.) was added portionwise with exotherm and controlled for T<After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours, 1L of an aqueous solution of sodium thiosulfate (150g) was added, the reaction mixture was stirred for 1 hour, the mixture was filtered and separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, 500mL of PE was added, the mixture was stirred and filtered to remove the residue, the solvent was removed by concentration, the mixture was distilled under reduced pressure with a water pump, and the fraction at 80 to 90 ℃ was collected to obtain 83g of a colorless liquid of the compound V-1 with a yield of 44.9%.1H-NMR(400MHz，CDCl3)(ppm)1.33-1.35(d，6H)，1.55-1.60(q，1H)，1.81-1.86(dd，1H)，1.94(s，1H)，2.48-2.50(m，1H)，2.80-2.82(t，1H)，3.11-3.16(m，1H)。
Preparation of Compound VI-1
Dissolving NaH (31.43g, 0.78mol, 1.1e.q.) in 400mL THF, dropwise adding benzyl alcohol (100mL) in an ice-water bath, stirring for reaction for 30min, dropwise adding a compound V-1(83.0g, 0.71mol, 1.0e.q.), stirring for reaction for 16h at room temperature after dropwise adding, adding 300mL water, separating liquid, extracting aqueous phases with EA, combining organic phases, washing with saturated saline solution, drying the organic phases, concentrating to prepare sand, purifying by column chromatography, concentrating to obtain 136.01g of a compound VI-1 as a yellow oily substance with the yield of 85%.1H-NMR(400MHz，CDCl3)(ppm)：4.57(s，2H)，4.19-4.25(m，1H)，3.44-3.47(m，1H)，3.37-3.41(m，1H)，3.26(s，2H)，1.67-1.73(m，1H)，1.52-1.53(d，1H)，1.32(s，3H)，1.27(s，3H)。
Preparation of Compound VII-1
VI-1(115g, 0.51mol, 1.0e.q.) was dissolved in 1L THF, cooled to 0 deg.C, n-BuLi (205mL, 0.51mol, 1.0e.q.) was added dropwise, the temperature was maintained for 20min, 500mL THF solution of TsCl (97.2g, 0.51mol, 1.0mol) was added dropwise, after the addition was complete, the temperature was raised to 10 deg.C, and the reaction was stirredCooling to 0 ℃ for 1h, dropwise adding n-BuLi (205mL, 0.51mol, 1.0e.q.), preserving heat for 30min, heating to 60 ℃, stirring for reaction for 16h, adding 1L of water, separating liquid, extracting the water phase with EA, combining organic phases, washing with saturated saline solution, drying, concentrating, preparing sand column chromatography, and purifying to obtain 87g of compound VII-1 yellow liquid with the yield of 86%.1H-NMR(400MHz，CDCl3)(ppm)：7.27-7.39(m，5H)，4.73-4.79(m，1H)，4.60-4.63(m，2H)，3.59-3.66(m，2H)，2.29-2.39(m，2H)，1.49(s，3H)，1.42(s，3H)。
Preparation of Compound I-1
Compound VII-1(26.0g, 0.126mol, 1.0e.q.) was dissolved in 1L MeOH, and 13g Pd (OH) was added2and/C, dropwise adding acetic acid and 3.5MPa hydrogen, reacting for 16h at 45 ℃ T, detecting by TLC that the raw materials completely react, cooling, filtering, concentrating the filtrate to remove the solvent, and distilling by a water pump under reduced pressure to collect 68-73 ℃ T to obtain 11.98g of the compound I-1 as a colorless transparent liquid with the yield of 82.05%.1H-NMR(400MHz，CDCl3)(ppm)：4.65-4.70(m，1H)，3.66-3.72(m，1H)，3.52-3.59(m，1H)，2.89-2.92(m，1H)，2.34-2.38(m，1H)，2.24-2.92(m，1H)，1.48(s，1H)，1.38(s，3H)。
Example 2
Preparation of Compound IV-2
Dissolving compound II-2(100g, 0.74mol, 1.0e.q.), compound III-1(133.5g, 1.11mol, 1.5e.q.) in 1.0L of water solution, adding Cu powder (94.04g, 1.48mol, 2.0e.q.) in portions, controlling T <50 ℃, stirring and reacting at room temperature for 3h after the addition is finished, filtering, washing a filter cake with MTBE, extracting the filter cake with aqueous MTBE, combining organic phases, washing the organic phases with 1L of saturated saline solution, drying, and concentrating to obtain compound IV-2 which is 71.73g of light yellow liquid with the yield of 55%.
Preparation of Compound V-2
Dissolving compound IV-2(70g, 0.39mol, 1.0e.q.) in 800mL of 1, 4-dioxane, adding tert-butyl peroxide (70.29g, 0.78mol, 2.0e.q.) in portions at-10 ℃, stirring and reacting for 16h at room temperature after adding, adding 1L of sodium thiosulfate (80g) aqueous solution, stirring and reacting for 1h, filtering and separating liquid, washing an organic phase with saturated saline, drying with anhydrous sodium sulfate, concentrating, adding 500mL of PE, filtering and removing residues after stirring, concentrating and removing a solvent, and performing sand making column chromatography to purify the compound V-2 to obtain 32.62g of a light yellow liquid with the yield of 43.5%.
Preparation of Compound VI-2
Dissolving 2.5M LDA (0.34mol, 2.0e.q.) in 136mL of THF solution, cooling to-50 ℃, dropwise adding benzyl alcohol (50mL), stirring for reaction for 30min, dropwise adding a compound V-2(32.62g, 0.17mol, 1.0e.q.), stirring for reaction at the temperature of 0 ℃ T for 4h after dropwise adding, adding 300mL of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline solution, drying the organic phase, concentrating to prepare sand, purifying by column chromatography, and concentrating to obtain 45.19g of a yellow oily compound VI-2 with the yield of 88.5%.
Preparation of Compound VII-2
VI-2(34.98g, 0.116mol, 1.0e.q.) is dissolved in 300mL THF, cooled to 0 ℃, added with potassium tert-butoxide (14.74g, 0.232mol, 2.0e.q.) in portions, kept warm for 20min, added with 200mL THF solution of MsCl (15.95g, 0.139mol, 1.2mol), heated to room temperature after the addition, stirred for reaction for 1h, cooled to 0 ℃, added with 1L water, separated, extracted with EA in water phase, combined with organic phase, washed with saturated saline, dried, concentrated for sand making, purified by column chromatography to obtain 27.84g of yellow liquid of a compound VII-2 with the yield of 85%.
Preparation of Compound I-2
Compound VII-2(14.74g, 0.0522mol, 1.0e.q.) was dissolved in 1L of MeOH, and 2g of Pd/C, ammonium formate (32.89g, 0.522mol, 10e.q.) and T ═ 50 ℃ were added for 16 h. LC-MS detects that the raw material disappears, the methanol is removed by reduced pressure rotary evaporation, and the compound I-2 is obtained by column chromatography purification of sand making column, and is light yellow solid 8.21g, and the yield is 88.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C11H14O2：178；found：179。
Example 3
Preparation of Compound IV-3
Compound II-3(100g, 0.507mol, 1.0e.q.) and compound III-3(106.7g, 1.52mol, 3.0e.q.) were dissolved in 800L of an aqueous solution of sodium acetate (80g), Mg powder (36.96g, 1.521mol, 3.0e.q.) was added in portions, the T <50 ℃ was controlled, after the addition was completed, the reaction was stirred at 40 ℃ for 8 hours, and the mixture was filtered, the cake was washed with MTBE, the aqueous phase was extracted with MTBE, the organic phases were combined, washed with 1L of saturated brine, and after drying, the mixture was concentrated to obtain 60.41g of compound IV-3 as a pale yellow liquid in 63.3% yield. Preparation of Compound V-3
Dissolving IV-3(60.0g, 0.318mol, 1.0e.q.) in 600mL of DCM solution, adding carbamide peroxide (87.81g, 0.956mol, 3.0e.q.) in portions at 0 ℃, releasing heat, controlling T <40 ℃, stirring and reacting at T < 10 ℃ for 16h after the addition is finished, adding 1L of sodium thiosulfate (100g) aqueous solution, stirring and reacting for 1h, filtering and separating liquid, washing an organic phase with saturated saline, drying anhydrous sodium sulfate and concentrating, adding 500mL of PE, stirring and filtering to remove residues, concentrating to remove a solvent, distilling under reduced pressure by a water pump, and purifying by sand making column chromatography to obtain a compound V-3 which is 29.74g of a light yellow liquid with the yield of 45.8%.
Preparation of Compound VI-3
2.0M NaHMDS (31.43g, 0.436mol, 3.0e.q.)218mL of THF solution is cooled to-10 ℃, benzyl alcohol (50mL) is added dropwise, after stirring reaction for 30min, compound V-3(29.74g, 0.146mol, 1.0e.q.) is added dropwise, after the addition, reaction is carried out at 0 ℃ T for 4h, 600mL of water is added, liquid separation is carried out, the aqueous phase is extracted by EA, the organic phase is combined, saturated saline is used for washing, after the organic phase is dried, sand preparation is carried out by concentration, purification is carried out by column chromatography, and the compound VI-3 is obtained by 36.71g of yellow solid through concentration, and the yield is 80.5%.
Preparation of Compound VII-3
Dissolving a compound VI-3(27.59g, 0.0883mol, 1.0e.q.) in 300mL of THF, cooling to 0 ℃, adding NaH (6.52g, 0.177mol, 2.0e.q.) in batches, adding 100mL of THF solution of trifluoromethanesulfonic anhydride (37.37g, 0.132mol, 1.5e.q.) dropwise, after the addition is finished, heating to 10 ℃, stirring for reaction for 1h, heating to 40 ℃, stirring for reaction for 18h, adding 1L of water, separating liquid, extracting an aqueous phase with EA, combining organic phases, washing with saturated common salt water, drying, concentrating, and purifying by column chromatography to obtain a compound VII-3 which is 20.88g of a yellow liquid with the yield of 80.3%.
Preparation of Compound I-3
Dissolving compound VII-3(10.48g, 0.0355mol, 1.0e.q.) in 1L MeOH, adding 1g Pd/C, dropwise adding acetic acid, 2MPa hydrogen, reacting at T ═ 10 ℃ for 28h, detecting by TLC that the raw materials are completely reacted, cooling, filtering, concentrating the filtrate to remove the solvent, and purifying by chromatography to obtain colorless pale yellow liquid 6.24g with the yield of 86.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C13H16O2：204；found：205。
Example 4
Preparation of Compound IV-4
Dissolving compound II-4(100g, 1.31mol, 1.0e.q.), compound III-4(281.4g, 3.26mol, 2.5e.q.) in 1.5 aqueous solution, adding aluminum trichloride (87.3g) at 0 ℃, stirring for 10min, adding Sn powder (387.0g, 3.26mol, 2.5e.q.) in portions, controlling T <50 ℃, stirring for 8h at room temperature after adding, filtering, washing filter cakes with MTBE, extracting aqueous MTBE, combining organic phases, washing with 1L saturated saline solution, drying, and concentrating to obtain compound IV-4 as light yellow liquid 77.76g with yield 46.3%.
Preparation of Compound V-4
Dissolving a compound IV-4(77.76g, 0.606mol and 1.0e.q.) in 600mL of DCM, dropwise adding hydrogen peroxide (137.5g, 1.21mol and 2.0e.q.) at-10 ℃, releasing heat, controlling the temperature T to be less than 40 ℃, stirring and reacting for 16h at room temperature after the addition is finished, adding 1L of sodium thiosulfate (150g) aqueous solution, stirring and reacting for 1h, filtering and separating liquid, washing an organic phase with saturated saline, drying and concentrating anhydrous sodium sulfate, adding 300mL of PE, stirring and filtering to remove residues, concentrating to remove a solvent, distilling under reduced pressure by a water pump, and collecting fractions at 95-100 ℃ to obtain 46.5g of a compound V-4 as a colorless liquid with the yield of 53.2%.
Preparation of Compound VI-4
Dissolving potassium tert-butoxide (102.4g, 1.61mol, 5.0e.q.) in 600mL of THF, adding benzyl alcohol (100mL) dropwise in an ice-water bath, stirring for reaction for 30min, then adding compound V-4(46.5g, 0.32mol, 1.0e.q.) dropwise, stirring for reaction at 60 ℃ T for 8h after the dropwise addition is finished, adding 900mL of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline, concentrating the organic phase to prepare sand after drying, purifying by column chromatography, and concentrating to obtain 61.17g of compound VI-4 as yellow oil with the yield of 75.8%. Preparation of Compound VII-4
Dissolving a compound VI-4(61.17g, 0.24mol and 1.0e.q.) in 1L THF, cooling to 0 ℃, dropwise adding 290mL THF solution of 2.5MLDA (0.73mol and 3.0 e.q), preserving heat for 30min, dropwise adding 500mL THF solution of p-nitrobenzenesulfonyl chloride (79.8g, 0.36mol and 1.5mol), after the addition is finished, heating to 50 ℃, stirring for reaction for 18h, adding 1.5L water, separating liquid, extracting the water phase with EA, combining the organic phases, washing with saturated saline water, drying, concentrating, purifying by a sand column chromatography to obtain 48.01g of a yellow liquid of the compound VII-4, wherein the yield is 85.3%.
Preparation of Compound I-4
Compound VII-4(25.0g, 0.106mol, 1.0e.q.) was dissolved in 1L of MeOH, 5g of Pd/C was added, formic acid 10g was added, T ═ 60 ℃ was reacted for 10h, TLC detected that the starting material was completely reacted, cooled and filtered, the filtrate was concentrated to remove the solvent, and then T ═ 85 to 90 ℃ was collected by water pump distillation under reduced pressure to give compound I-4 as a colorless transparent liquid 12.54g with yield 82.05%. (ESI-TOF) m/z: [ M + H ]]+calcd for C8H16O2：144；found：145。
Example 5
Preparation of Compound IV-5
Dissolving compound II-1(100g, 0.83mol, 1.0e.q.) and compound III-5(243.3g, 2.47mol, 3.0e.q.) in 1.5 aqueous solution, adding aluminum trichloride (50g) at-10 ℃, stirring for 20min, adding aluminum powder (66.69g, 2.47mol, 3.0e.q.) in batches, controlling T <50 ℃, stirring and reacting at room temperature for 10h after the addition is finished, filtering, washing a filter cake with MTBE, extracting an aqueous phase with MTBE, combining organic phases, washing with 1L of saturated common salt water, drying, and concentrating to obtain 59.7g of compound IV-5 as a light yellow liquid with the yield of 51.3%.
Preparation of Compound V-5
Compound IV-5(59.7g, 0.425mol, 1.0e.q.) was dissolved in 600mL of DCM, m-CPBA (86.43g, 0.425mol, 1.0e.q.) was added in portions, heat was released, T <40 ℃ was controlled, after the addition, T ═ 20 ℃ was stirred and reacted for 15 hours, 1L of an aqueous solution of sodium thiosulfate (150g) was added, the reaction was stirred for 1 hour, liquid separation was performed by filtration, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, 500mL of PE was added, the residue was removed by filtration after stirring, the solvent was removed by concentration, and the distillate at 100 to 105 ℃ was collected by water pump distillation under reduced pressure to obtain 36.45g of compound V-5 as a colorless liquid with a yield of 54.9%. Preparation of Compound VI-5
The preparation method comprises the steps of cooling 408mL of THF solution of 2.0M LiHMDS (31.43g, 0.816mol and 3.5e.q.) to-10 ℃, dropwise adding benzyl alcohol (50mL), stirring for reaction for 30min, dropwise adding a compound V-5(36.45g, 0.233mol and 1.0e.q.), stirring for reaction for 8h at room temperature after dropwise adding, adding 300mL of water, separating, extracting an aqueous phase with EA, combining organic phases, washing with saturated saline solution, drying an organic phase, concentrating, purifying by column chromatography, and concentrating to obtain 46.38g of a compound VI-5 as yellow oily matter with the yield of 75.3%.
Preparation of Compound VII-5
Dissolving a compound VI-5(46.38g, 0.175mol, 1.0e.q.) in 500mL of THF, cooling to 0 ℃, dropwise adding a 2.5M NaHMDS (0.438mol, 2.5e.q.)175mL of THF solution, preserving heat for 20min, dropwise adding a TsCl (66.7g, 0.35mol, 2.0e.q.) 500mL of THF solution, stirring for reaction for 1h after the addition is finished, heating to 50 ℃, stirring for reaction for 16h, adding 1L of water, separating, extracting an aqueous phase by EA, combining organic phases, washing by using saturated saline water, drying, concentrating, performing sand column chromatography and purifying to obtain a compound VII-5 yellow liquid 36.31g, wherein the yield is 84.2%.
Preparation of Compound I-5
Compound VII-5(19.06g, 0.077mol, 1.0e.q.) was dissolved in 200mL MeOH, and added2g of Pd (OH)2and/C, dropwise adding acetic acid and 3.5MPa hydrogen, reacting for 20h at 55 ℃ T, detecting by TLC that the raw materials completely react, cooling, filtering, concentrating the filtrate to remove the solvent, and distilling under reduced pressure by a water pump to collect 90-98 ℃ T to obtain 10.26g of the compound I-5 as a colorless transparent liquid, wherein the yield is 85.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C9H16O2：156；found：157。
Example 6
Preparation of Compound IV-6
Compound II-5(100g, 0.473mol, 1.0e.q.) and compound III-6(14.20g, 0.473mol, 1.0e.q.) were dissolved in 600L of an aqueous solution of ammonium chloride (30g), Zn powder (30.75g, 0.473mol, 1.0e.q.) was added in portions, the temperature T <50 ℃ was controlled, after the addition was completed, the reaction was stirred at 40 ℃ T for 18 hours, filtered, the cake was washed with MTBE, the aqueous phase was extracted with MTBE, the organic phases were combined, washed with 1L of saturated brine, dried and concentrated to give compound IV-6 as a pale yellow liquid 46.27g, with a yield of 60.3%. Preparation of Compound V-6
Compound IV-6(46.27g, 0.285mol, 1.0e.q.) was dissolved in 400mL of DCM solution, cumene hydroperoxide (86.82g, 0.57mol, 2.0e.q.) was added in portions at 0 ℃, heat was released, T <40 ℃ was controlled, after the addition, T ═ 10 ℃ was stirred and reacted for 18 hours, 1L of an aqueous solution of sodium thiosulfate (100g) was added, after the reaction was stirred for 1 hour, the mixture was separated by filtration, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, 300mL of PE was added, after the stirring, the residue was removed by filtration, after the solvent was removed by concentration, distillation was performed under reduced pressure using a water pump, and purification by column chromatography was performed to obtain compound V-6 as a pale yellow liquid 24.79g, with a yield of 48.8%.
Preparation of Compound VI-6
Cooling 2.5M n-butyllithium (0.556mol, 4.0e.q.)222mL of n-hexane solution to-78 ℃, dropwise adding benzyl alcohol (50mL), stirring for reaction for 30min, dropwise adding a compound V-6(24.79g, 0.139mol, 1.0e.q.), stirring for reaction at-40 ℃ for 2h after dropwise adding, adding 600mL of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline, drying the organic phase, concentrating to prepare sand, purifying by column chromatography, and concentrating to obtain a compound VI-6 which is 26.07g of yellow solid with the yield of 65.5%.
Preparation of Compound VII-6
Dissolving a compound VI-6(26.07g, 0.091mol, 1.0e.q.) in 300mL of THF, cooling to 0 ℃, adding NaH (3.36g, 0.091mol, 1.0e.q.) in batches, adding 100mL of THF solution of methanesulfonic anhydride (15.85g, 0.091mol, 1.0e.q.) dropwise, after the addition is finished, heating to room temperature, stirring for reaction for 1h, heating to 60 ℃, stirring for reaction for 12h, adding 1L of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline water, drying, concentrating, and purifying by column chromatography to obtain a compound VII-6 which is 20.59g of yellow liquid with the yield of 84.3%.
Preparation of Compound I-6
Dissolving compound VII-6(10.81g, 0.0403mol, 1.0e.q.) in 1L MeOH, adding 1g Pd/C, dropwise adding acetic acid and 2MPa hydrogen, reacting at 50 ℃ T for 20h, detecting by TLC that the raw materials are completely reacted, cooling, filtering, concentrating the filtrate to remove the solvent, and purifying by sand column chromatography to obtain compound I-6 as a light yellow liquid 6.33g with the yield of 88.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C11H14O2：178；found：179。
Example 7
Preparation of Compound IV-7
Dissolving compound II-1(100g, 0.82mol, 1.0e.q.) and compound III-1(167.01g, 1.24mol, 1.5e.q.) in 1.0L of aqueous solution, adding Cu powder (104.2g, 1.64mol, 2.0e.q.) in portions, controlling the temperature T <50 ℃, stirring and reacting at room temperature for 3 hours after the addition is finished, filtering, washing a filter cake with MTBE, extracting the filter cake with aqueous MTBE, combining organic phases, washing the organic phases with 1L of saturated saline solution, drying, and concentrating to obtain compound IV-7 which is 93.94g of light yellow liquid with the yield of 65%.
Preparation of Compound V-7
Dissolving compound IV-7(93.94g, 0.53mol, 1.0e.q.) in 800mL of 1, 4-dioxane, adding tert-butyl peroxide (96.07g, 1.06mol, 2.0e.q.) in portions at-10 ℃, stirring for reaction at room temperature for 18h after the addition is finished, adding 1L of sodium thiosulfate (80g) aqueous solution, stirring for reaction for 1h, filtering for liquid separation, washing an organic phase with saturated saline, drying anhydrous sodium sulfate, concentrating, adding 500mL of PE, filtering for residue after stirring, concentrating for solvent removal, and purifying by sand making column chromatography to obtain compound V-7 as a pale yellow liquid 54.51g with the yield of 53.5%.
Preparation of Compound VI-7
2.5M LDA (0.567mol, 2.0e.q.) is dissolved in 227mL THF solution, cooled to-50 ℃, benzyl alcohol (50mL) is added dropwise, after stirring reaction for 30min, compound V-7(54.51g, 0.283mol, 1.0e.q.) is added dropwise, after the dropwise addition, T is 0 ℃ and stirring reaction is carried out for 5h, 400mL water is added, liquid separation is carried out, aqueous phase is extracted by EA, organic phase is combined, saturated saline solution is used for washing, after organic phase is dried, sand is concentrated and purified by column chromatography, and compound VI-7 is obtained by concentration as yellow oily matter 59.93g, and the yield is 70.5%.
Preparation of Compound VII-7
Dissolving a compound VI-7(59.93g, 0.199mol, 1.0e.q.) in 500mL of THF, cooling to 0 ℃, adding potassium tert-butoxide (25.29g, 0.398mol, 2.0e.q.) in batches, preserving heat for 20min, dropwise adding 400mL of THF solution of MsCl (60.7g, 0.318mol, 1.6mol), after the addition is finished, heating to 25 ℃, stirring for reaction for 1h, cooling to 0 ℃, adding 1L of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline, drying, concentrating, purifying by sand column chromatography to obtain 47.75g of a yellow liquid of the compound VII-7, wherein the yield is 85%.
Preparation of Compound I-7
Compound VII-7(30.90g, 0.109mol, 1.0e.q.) was dissolved in 300mL MeOH, and 3g Pd/C, ammonium formate (68.67g, 1.09mol, 10e.q.) and T ═ 50 ℃ were added for 16 h. LC-MS detects that the raw material disappears, the methanol is removed by reduced pressure rotary evaporation, and the compound I-7 is obtained by column chromatography purification of sand making column, and is light yellow solid 16.40g, and the yield is 78.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C12H16O2：192；found：193。
Example 8
Preparation of Compound IV-8
Compound II-1(100g, 0.83mol, 1.0e.q.), compound III-8(278.1g, 2.47mol, 3.0e.q.) -were dissolved in a 1.5 aqueous solution, aluminum trichloride (50g) was added at 0 ℃, after stirring for 20min, aluminum powder (66.69g, 2.47mol, 3.0e.q.) was added in portions, T <50 ℃ was controlled, after completion of the addition, T ═ 40 ℃ was stirred for reaction for 6h, filtration was performed, the cake was washed with MTBE, the aqueous phase MTBE was extracted, the organic phase was combined, washed with 1L of saturated brine, dried and concentrated to obtain 78.47g of compound IV-8 as a pale yellow liquid with a yield of 61.3%.
Preparation of Compound V-8
Dissolving a compound IV-8(78.47g, 0.508mol, 1.0e.q.) in 600mL of DCM, adding m-CPBA (206.3g, 1.02mol, 2.0e.q.) in portions, releasing heat, controlling the temperature T <40 ℃, stirring and reacting for 15h at the temperature T ═ 20 ℃ after the addition is finished, adding 1L of sodium thiosulfate (150g) aqueous solution, stirring and reacting for 1h, filtering and separating liquid, washing an organic phase with saturated saline, drying anhydrous sodium sulfate and concentrating, adding 500mL of PE, stirring and filtering to remove residues, concentrating to remove a solvent, distilling under reduced pressure by a water pump, and collecting fractions at 100-105 ℃ to obtain a compound V-8 which is 56.12g of a colorless liquid, wherein the yield is 64.9%. Preparation of Compound VI-8
Cooling a 2.0M LiHMDS (0.66mol, 2.0e.q.)330mL THF solution to-10 ℃, dropwise adding benzyl alcohol (50mL), stirring for reaction for 30min, dropwise adding a compound V (56.12g, 0.33mol, 1.0 e.q), after dropwise adding, stirring for reaction at a temperature of T-20 ℃ for 8h, adding 300mL water, separating, extracting an aqueous phase with EA, combining organic phases, washing with saturated saline, drying an organic phase, concentrating, purifying by column chromatography to obtain a compound VI-8, which is 71.93g of yellow oily matter, and obtaining the yield of 78.3%.
Preparation of Compound VII-8
Dissolving a compound VI-8(71.93g, 0.258mol, 1.0e.q.) in 700mL of THF, cooling to 0 ℃, dropwise adding a 2.5M LiHMDS (0.855mol, 3.0e.q.)342mL of THF solution, preserving heat for 20min, dropwise adding a TsCl (98.37g, 0.516mol, 2.0mol) 500mL of THF solution, stirring for reaction for 1h after adding, heating to 50 ℃, stirring for reaction for 16h, adding 1L of water, separating liquid, extracting an aqueous phase with EA, combining organic phases, washing with saturated common salt, drying, concentrating, carrying out sand column chromatography purification to obtain a compound VII-8 yellow liquid 56.56g, wherein the yield is 84.2%.
Preparation of Compound I-8
Compound VII-8(36.41g, 0.139mol, 1.0e.q.) was dissolved in 400mL EtOH, 2g Pd (OH) was added2And C, dropwise adding acetic acid and 3.5MPa hydrogen, reacting for 20h at 55 ℃ T, detecting by TLC that the raw materials are completely reacted, cooling and filtering, concentrating the filtrate to remove the solvent, and then performing reduced pressure distillation by a water pump to collect 110 ℃ T, 105 and 110 ℃ T to obtain 17.82g of the compound I-8 which is a colorless transparent liquid, wherein the yield is 75.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C10H18O2：170；found：171。
Example 9
Preparation of Compound IV-9
Dissolving compound II-1(100g, 0.82mol, 1.0e.q.) and compound III-9(226.0g, 1.24mol, 1.5e.q.) in 1.0L of aqueous solution, adding Cu powder (104.2g, 1.64mol, 2.0e.q.) in portions, controlling the temperature T <50 ℃, stirring and reacting at room temperature for 4 hours after the addition is finished, filtering, washing a filter cake with MTBE, extracting the MTBE in an aqueous phase, combining organic phases, washing the organic phases with 1L of saturated saline solution, drying, concentrating, preparing sand column chromatography and purifying to obtain 81.7g of compound IV-9 as a light yellow attached substance with the yield of 45%.
Preparation of Compound V-9
Dissolving compound IV-9(82.7g, 0.369mol, 1.0e.q.) in 800mL of 1, 4-dioxane, adding tert-butyl peroxide (66.51g, 0.738mol, 2.0e.q.) in portions at-10 ℃, stirring for reaction at room temperature for 8h after the addition is finished, adding 1L of sodium thiosulfate (80g) aqueous solution, stirring for reaction for 1h, filtering for liquid separation, washing an organic phase with saturated saline, drying anhydrous sodium sulfate, concentrating, adding 500mL of PE, filtering for residue after stirring, concentrating for solvent removal, and purifying by sand making column chromatography to obtain compound V-9 as a light yellow solid, 29.7g, and the yield is 33.5%.
Preparation of Compound VI-9
Dissolving 2.5M LDA (0.247mol, 2.0e.q.) in 99mL of THF solution, cooling to-50 ℃, dropwise adding benzyl alcohol (50mL), stirring for reaction for 30min, dropwise adding compound V-9(29.7g, 0.123mol, 1.0e.q.), stirring for reaction at 0 ℃ T for 8h after dropwise adding, adding 300mL of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline solution, drying the organic phase, concentrating to prepare sand, purifying by column chromatography, concentrating to obtain 43.46g of compound VI-9 as yellow oily matter with the yield of 50.5%.
Preparation of Compound VII-9
Dissolving a compound VI-9(43.46g, 0.124mol, 1.0e.q.) in 400mL of THF, cooling to 0 ℃, adding potassium tert-butoxide (15.85g, 0.249mol, 2.0 e.q) in batches, preserving heat for 20min, dropwise adding a 200mL THF solution of MsCl (25.57g, 0.223mol, 1.8mol), after the addition is finished, heating to room temperature, stirring for reaction for 2h, cooling to 0 ℃, adding 1L of water, separating, extracting the water phases with EA, combining the organic phases, washing with saturated saline, drying, concentrating, purifying by sand column chromatography to obtain 22.52g of a yellow compound VII-9 liquid with the yield of 55%.
Preparation of Compound I-9
Compound VII-9(22.52g, 0.0682mol, 1.0e.q.) was dissolved in 200mL MeOH, and 2g Pd/C, ammonium formate (42.97g, 0.682mol, 10e.q.) and T ═ 60 ℃ were added and reacted for 18 h. LC-MS detects that the raw material disappears, the methanol is removed by reduced pressure rotary evaporation, and the compound I-9 is obtained by column chromatography purification of sand making column as light yellow solid 8.55g, and the yield is 58.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C16H16O2：240；found：241。
Example 10
Preparation of Compound IV-10
Compound II-3(100g, 0.507mol, 1.0e.q.), compound III-6(53.85g, 0.507mol, 1.0e.q.) were dissolved in 600L of an aqueous solution of ammonium chloride (30g), Zn powder (32.96g, 0.507mol, 1.0e.q.) was added in portions, after T <50 ℃ was controlled, the reaction was stirred at 40 ℃ T for 10 hours, filtered, the cake was washed with MTBE, the aqueous phase was extracted with MTBE, the organic phases were combined, washed with 1L of saturated brine, dried and concentrated to obtain 45.83g of compound IV-10 as a pale yellow liquid with a yield of 40.3%. Preparation of Compound V-10
Dissolving compound IV-10(45.83g, 0.204mol, 1.0e.q.) in 400mL of DCM solution, adding cumene hydroperoxide (62.19g, 0.408mol, 2.0e.q.) in portions at 0 ℃, releasing heat, controlling T <40 ℃, after the addition is finished, stirring and reacting at 10 ℃ for 28h, adding 1L of sodium thiosulfate (100g) aqueous solution, stirring and reacting for 1h, filtering, separating liquid, washing an organic phase with saturated common salt water, drying anhydrous sodium sulfate, concentrating, adding 300mL of PE, stirring, filtering to remove residues, concentrating to remove a solvent, distilling under reduced pressure by a water pump, and purifying by sand column chromatography to obtain 21.47g of compound V-10 as a light yellow liquid with the yield of 43.8%.
Preparation of Compound VI-10
Cooling a 2.5M n-butyllithium (0.268mol, 3.0e.q.)107mL of n-hexane solution to-78 ℃, dropwise adding benzyl alcohol (50mL), stirring for reaction for 30min, dropwise adding a compound V-10(21.47g, 0.0893mol, 1.0 e.q), after dropwise adding, stirring for reaction at-40 ℃ for 4h, adding 600mL of water, separating, extracting the water phase with EA, combining the organic phases, washing with saturated saline, drying the organic phase, concentrating to prepare sand, purifying by column chromatography, and concentrating to obtain a compound VI-10 which is 15.71g of yellow solid with the yield of 50.5%.
Preparation of Compound VII-10
Dissolving a compound VI-10(15.71g, 0.045mol, 1.0e.q.) in 200mL THF, cooling to 0 ℃, adding NaH (1.67g, 0.045mol, 1.0e.q.) in batches, adding a 50mL THF solution of methanesulfonic anhydride (7.84g, 0.045mol, 1.0e.q.) dropwise, after the addition is finished, heating to room temperature, stirring for reaction for 1h, heating to 60 ℃, stirring for reaction for 16h, adding 1L water, separating, extracting an aqueous phase with EA, combining organic phases, washing with saturated saline, drying, concentrating, and purifying by column chromatography to obtain a compound VII-10 which is 8.07g of a yellow liquid with the yield of 54.3%.
Preparation of Compound I-10
Dissolving compound VII-10(8.07g, 0.0244mol, 1.0e.q.) in 200L MeOH, adding 1g Pd/C, adding one drop of acetic acid, 2MPa hydrogen, reacting at 50 deg.C for 20h, detecting by TLC that the raw materials are completely reacted, cooling, filtering, concentrating the filtrate to remove the solvent, and purifying by chromatography to obtain compound I-10 as light yellow liquid 3.42g with yield of 58.3%. (ESI-TOF) m/z: [ M + H ]]+calcd for C16H16O2：240；found：241。
Claims (11)
1. A process for the preparation of a synthetic compound I comprising:
wherein: r1、R2、R3Are respectively and independently selected from hydrogen, C1-C5 straight-chain alkyl, phenyl, substituted phenyl or R2And R3Saturated cycloalkyl of C4-C7 or substituted saturated cycloalkyl of C4-C7; wherein R is1、R2、R3At least one is hydrogen; the substituent of the substituted phenyl is a C1-C5 straight-chain alkyl; the substituent of the substituted saturated naphthenic base is a C1-C5 straight-chain alkyl;
in the step of preparing compound VII from compound VI, the base is: sodium hydride, potassium hydride, calcium hydride, lithium diisopropylamide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium tert-butoxide, or sodium tert-butoxide; the sulfonyl chloride/sulfonic anhydride is as follows: p-toluenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonic anhydride or trifluoromethanesulfonic anhydride; the molar ratio of the compound VI to the base to the sulfonyl chloride/sulfonic anhydride is 1: 1-3: 1-2; the reaction temperature range is 0-60 ℃.
2. The method of claim 1, comprising:
wherein: r1、R2、R3Are respectively and independently selected from hydrogen, C1-C5 straight-chain alkyl, phenyl, substituted phenyl or R2And R3Saturated cycloalkyl of C4-C7 or substituted saturated cycloalkyl of C4-C7; wherein R is1、R2、R3At least one is hydrogen; the substituent of the substituted phenyl is a C1-C5 straight-chain alkyl; the substituent of the substituted saturated naphthenic base is a C1-C5 straight-chain alkyl; x is chlorine or bromine.
3. The method of claim 2, wherein: in the step of preparing the compound IV from the compound II and the compound III, ammonium chloride, sodium acetate or aluminum chloride is added in the reaction.
4. The method of claim 2, wherein: in the step of preparing the compound IV from the compound II and the compound III, the metal is copper, magnesium, aluminum, tin and zinc.
5. The production method according to claim 2 or claim 4, characterized in that: in the step of preparing the compound IV from the compound II and the compound III, the molar ratio of the compound II to the compound III to the metal is 1: 1-3; the reaction temperature is in the range of-10 to 50 ℃.
6. The method of claim 2, wherein: in the step of preparing compound V from compound IV, the peroxide is: meta-chloroperoxybenzoic acid, t-butyl peroxide, cumene hydroperoxide, urea peroxide, or hydrogen peroxide.
7. The production method according to claim 2 or claim 6, characterized in that: in the step of preparing the compound V from the compound IV, the reaction temperature ranges from-10 ℃ to 40 ℃.
8. The production method according to claim 1 or claim 2, characterized in that: in the step of preparing compound VI from compound V, the base is: sodium hydride, potassium hydride, calcium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, or potassium bis (trimethylsilyl) amide.
9. The method of claim 8, wherein: in the step of preparing the compound VI from the compound V, the reaction temperature ranges from-78 ℃ to 60 ℃.
10. The production method according to claim 1 or claim 2, characterized in that: in the step of preparing the compound I from the compound VII, the catalyst is palladium carbon or palladium hydroxide carbon; the reducing agent is hydrogen, formic acid or ammonium formate.
11. The method of manufacturing according to claim 10, wherein: in the step of preparing the compound I from the compound VII, the reaction temperature ranges from 10 ℃ to 60 ℃.
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