CN108276408B - Intermediate of trabectedin, preparation method and application thereof - Google Patents
Intermediate of trabectedin, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a key intermediate compound A for preparing trabectedin and a method for preparing the compound A from a compound D. The invention also relates to the reduction of the compound A to prepare the compoundE, the method is controllable, simple and convenient to operate and stable in yield.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a key intermediate for preparing a medicine, namely, trobestatin, for treating advanced soft tissue sarcoma, and a preparation method and application thereof.
Background
Tribetidine (trade name Yondelis), developed by Qiangsheng pharmaceutical Co., Ltd., is a natural product isolated from the marine organism Ecteinascidia turbinata, but its content is extremely low, only 10-6～10-7% w/w. Tributine was listed as a rare drug for soft tissue sarcoma in the European Union in 2001, and became the first modern marine drug. In 2004, the drug was classified by the U.S. Food and Drug Administration (FDA) as a rare drug for soft tissue sarcoma, and in europe and america, it was designated as an orphan drug for the treatment of acute lymphoblastic leukemia, soft tissue sarcoma, and ovarian cancer. In addition to blocking the differentiation of tumor cells in the G1/G2 cycle, trabectedin can also inhibit the secretion of Vascular Endothelial Growth Factor (VEGF) and the expression of its receptor.
Methods for the total synthesis of trabectedin are disclosed in US8058435, WO2007045686a2 and j.am.chem.soc, 2006,128(1), 87-89. As shown in the attached figure 1, the compound 1 is used as a key intermediate for preparing the trabectedin, and is prepared by 6 steps of reduction, upper protection, deprotection, oxidation, cyclization and deprotection of a compound 7, the steps are long, the total yield is 56.8%, and the feeding amount of the disclosed embodiment is small and is only in the order of hundred milligrams. In addition, the inventor found in experiments that when compound 6 is prepared by reducing compound 7, the reaction is greatly affected by the way of feeding methanol and the reaction temperature: if the dropping speed is slightly high or the temperature of the reaction system is higher than 0 ℃, a large amount of cyano reduction byproducts are generated due to the relatively impurity reaction system, particularly in an amplification experiment, the phenomenon that the reaction system becomes impurity is particularly obvious due to the fact that local heat effect and concentration are not uniform when methanol is dropped; if the dropping speed is slow or the temperature of the reaction system is lower than 0 ℃, the reduction reaction is very slow, the conversion rate is low, the reaction time is too long, and the generation of a cyano reduction byproduct can still be detected. In view of the above disadvantages of the existing synthetic methods for preparing the compound 1, a new economic, efficient, simple and controllable route is needed to be developed, which is beneficial to industrial production.
Disclosure of Invention
The first object of the present invention is to provide a key intermediate compound a for preparing trabectedin, or stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates and pharmaceutically acceptable salts thereof:
wherein R is1And R2Each independently selected from hydrogen, straight or branched C1-6Alkyl, optionally substituted by C1-6Alkoxy-substituted benzyloxy group C1-6Alkyl, optionally substituted by C1-6Alkoxy-or nitro-mono-or polysubstituted benzyl, C optionally substituted by halogen1-6Alkoxycarbonyl group, C3-6Alkenyloxycarbonyl, allyl, OR OR1、OR2Taken together to form-OCH2O-；
Preferably, said straight or branched C1-6Alkyl is selected from methyl and ethyl; said optional quilt C1-6Alkoxy-substituted benzyloxy group C1-6Alkyl is selected from Benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM); optionally is covered with C1-6The alkoxy or nitro mono-or polysubstituted benzyl is selected from the group consisting of p-methoxybenzyl (MPM), 3, 4-dimethoxybenzyl
(DMPM), o-nitrobenzyl, p-nitrobenzyl; said C optionally substituted by halogen1-6Alkoxycarbonyl selected from 2,2,2-
Trichloroethoxycarbonyl (Troc); said C is3-6The alkenyloxycarbonyl group is selected from allyloxycarbonyl (Alloc).
Further preferably, OR1、OR2Taken together to form-OCH2O-；
R3Selected from straight or branched C1-6Alkyl groups, preferably selected from methyl and ethyl.
R4For protection of amino groupsThe amino protecting group is selected from linear or branched C1-6Alkyl, C optionally substituted by halogen1-6Alkoxycarbonyl group, C3-6Alkenyloxycarbonyl, allyl; preferably, R4Selected from the group consisting of methyl, ethyl, allyloxycarbonyl (Alloc), Allyl (alyl) and 2,2, 2-trichloroethoxycarbonyl (Troc).
R5Is straight-chain or branched C1-6Alkyl, optionally substituted by C1-6Alkoxy-substituted benzyloxy group C1-6Alkyl, optionally substituted by C1-6Alkoxy-or nitro-mono-or polysubstituted benzyl, C optionally substituted by halogen1-6Alkoxycarbonyl group, C3-6Alkenyloxycarbonyl or allyl; preferably, R5Selected from the group consisting of methyl, ethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, allyloxycarbonyl (Alloc), Allyl (Allyl), 2,2, 2-trichloroethoxycarbonyl (Troc).
It is another object of the present invention to provide a method for the synthesis of compounds of formula a, which can be represented by the following scheme:
wherein R is1-R5As defined above.
R1' and R2' Each is independently selected from straight or branched C1-6Alkyl, optionally substituted by C1-6Alkoxy-substituted benzyloxy group C1-6Alkyl, optionally substituted by C1-6Alkoxy-or nitro-mono-or polysubstituted benzyl, C optionally substituted by halogen1-6Alkoxycarbonyl group, C3-6Alkenyloxycarbonyl, allyl, optionally substituted by C1-6Alkylsilyl or halogen or C1-6Alkoxy-substituted C1-6Alkoxy radical C1-6Alkyl, OR OR1’、OR2' Co-constituent-OCH2O-; with the proviso that when R1' or R2' is optionally substituted by C1-6Alkylsilyl or halogen or C1-6Alkoxy-substituted C1-6Alkoxy radicalC1-6When alkyl, the corresponding R1Or R2Is H; when R is1' or R2' is straight-chain or branched C1-6Alkyl, optionally substituted by C1-6Alkoxy-substituted benzyloxy group C1-6Alkyl, optionally substituted by C1-6Alkoxy-or nitro-mono-or polysubstituted benzyl, C optionally substituted by halogen1-6Alkoxycarbonyl group, C3-6Alkenyloxycarbonyl, allyl, OR OR1’、OR2' Co-constituent-OCH2When O is-O, R1' or R2' respectively with R1Or R2The same;
R6selected from the group consisting of1-6Alkylsilyl or halogen or C1-6Alkoxy-substituted C1-6Alkoxy radical C1-6Alkyl, preferably selected from the group consisting of methoxymethyl (MOM), tert-butoxymethyl, 1-ethoxyethyl (EE), 2,2, 2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM) and 2- (trimethylsilyl) ethoxymethyl (SEM).
R7Selected from straight or branched C3-9The alkylsilyl group is preferably selected from Trimethylsilyl (TMS), Triethylsilyl (TES), t-butyldimethylsilyl (TBS) and Triisopropylsilyl (TIPS), more preferably t-butyldimethylsilyl.
More specifically, the preparation method of the compound A comprises the following steps:
(1) dissolving the compound D in an organic solvent at room temperature, dropwise adding a deprotection reagent, and stirring until the detection raw materials completely react after dropwise adding; wherein the deprotection reagent is preferably selected from hydrogen fluoride water solution, pyridine hydrogen fluoride and triethylamine hydrogen trifluoride, more preferably pyridine hydrogen fluoride, and the feeding molar ratio of the deprotection reagent to the compound D is preferably 5-20:1, more preferably 15: 1; the organic solvent is preferably selected from acetonitrile, tetrahydrofuran, dichloromethane or any combination thereof;
(2) at room temperature, the compound C is reacted with an oxidant to prepare a compound B; the oxidation reaction is a conventional oxidation method in the field, and the used oxidizing agent is a conventional oxidizing agent in the field, and preferably can be selected from Des-Martin oxidizing agent and 2-iodoxybenzoic acid; the feeding molar ratio of the oxidant to the compound C is preferably 1-5:1, more preferably 3: 1; the reaction solvent is preferably dichloromethane, tetrahydrofuran, toluene, acetonitrile or any combination thereof;
(3) adding a solution of acid in an organic solvent into the compound B at room temperature under the protection of inert gas, and stirring until the raw materials react completely to obtain a compound A; the acid is preferably selected from trifluoroacetic acid, sulfuric acid, hydrochloric acid, acetic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid, more preferably trifluoroacetic acid; the feeding molar ratio of the acid to the compound B is preferably 3-10: 1; the volume ratio of the acid to the organic solvent is preferably 1: 100-500; the organic solvent is preferably selected from dichloromethane, acetonitrile, tetrahydrofuran, toluene or any combination thereof.
In the above reaction, the steps 1 to 3 can be continuously operated without separate separation and purification.
Compound D may be prepared according to the methods disclosed in j.am.chem.soc.,2006,128(1), 87-89.
It is a further object of the present invention to provide a process for the preparation of compound E from compound a, which can be represented by the following scheme:
wherein R is1-R5As defined above.
More specifically, the preparation method of the compound E comprises the following steps:
step 4, dissolving methanol in a first organic solvent for later use; under the protection of inert gas, dissolving the compound A in a second organic solvent, cooling to 0 ℃, adding a reducing agent, adding the prepared methanol solution in batches, keeping the temperature of the system not more than 10 ℃, and stirring until the raw materials react completely to obtain a compound E; the feeding batch number is preferably 2-10 times, the feeding time interval between batches is preferably not less than 10 minutes, the reducing agent is preferably selected from lithium borohydride, sodium borohydride and lithium aluminum hydride, and more preferably is selected from lithium borohydride; the feeding molar ratio of the reducing agent to the compound A is preferably 1-10: 1; the volume ratio of the first organic solvent to the methanol is preferably 10-40: 1; the feeding molar ratio of the methanol to the compound A is preferably 3-20: 1; the molar concentration of the compound A in the second organic solvent is preferably 0.1-0.25 mol/L; the first organic solvent and the second organic solvent are preferably each independently selected from tetrahydrofuran, acetonitrile, dichloromethane, toluene, or any combination thereof.
The invention has the advantages that:
1. the method for preparing the compound A from the compound D has the advantages that three steps of reactions can be continuously operated, independent separation and purification are not needed, the operation is simple and convenient, and the amplification is easy;
2. by adopting the method for preparing the compound E by using the compound A, the methanol adding mode is changed, the reaction is controllable, the operation is simple and convenient, a cyano reduction by-product is not detected during an amplification test, and the yield is stable;
3. compared with the prior art, the method for preparing the compound E from the compound D shortens the reaction steps, improves the yield to 83 percent, stabilizes the reaction process, shortens the product period, reduces the reaction cost and is beneficial to large-scale production.
Drawings
FIG. 1 shows a total synthesis method of trabectedin as disclosed in J.am.chem.Soc.,2006,128(1), 87-89.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Operations or steps not specifically indicated in the following examples are generally carried out according to conventional conditions in the art.
The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.
The room temperatures stated in the examples are all 5-35 ℃. Unless otherwise indicated, the reagents were used without purification and all solvents were purchased from commercial suppliers. The reaction was judged for termination by TLC analysis and/or by LC-MS analysis by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, developed with UV light (254nm) and/or iodine on silica gel, and/or heated with TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or ceric sulfate solution.
1H-NMR spectra were recorded on a Varian Mercury-VX400 instrument at 400MHz operation.
Abbreviations used in the present invention have conventional meanings in the art. Wherein TMS is trimethylsilyl, TBS is tert-butyldimethylsilyl, TES is triethylsilyl, TIPS is triisopropylsilyl, MOM is methoxymethyl, EE is 1-ethoxyethyl, MEM is 2-methoxyethoxymethyl, SEM is 2- (trimethylsilyl) ethoxymethyl, BOM is benzyloxymethyl, PMBM is p-methoxybenzyloxymethyl, MPM is methoxybenzyl, DMPM is 3, 4-dimethoxybenzyl, Alloc is allyloxycarbonyl, Allyl is Allyl, Troc is 2,2, 2-trichloroethoxycarbonyl, THF is tetrahydrofuran, DCM is dichloromethane, and TFA is trifluoroacetic acid.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Example 1: preparation of Compound C-1
Compound D-1(34g, 42.08mmol) was dissolved in acetonitrile (500mL) at room temperature, pyridine hydrogen fluoride (62.55g, 0.631mol) was added, the reaction mixture was stirred at room temperature until TLC monitored that the starting material reaction was complete, the reaction mixture was diluted with dichloromethane (1.5L), washed successively with saturated sodium bicarbonate solution (500mL) and saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, concentrated, crude flash column chromatography (ethyl acetate: petroleum ether: 1:4), concentrated to give compound C-1(28g, yield: 96%,1H-NMR(400MHz,CDCl3)：6.59-6.58(s,1H),6.20(s,1H),6.18-6.10(m,1H),5.88-5.81(m,1H),5.80(s,1H),5.66(s,1H),5.60-4.99(m,6H),4.81-4.52(m,7H),4.23(m,3H),3.88-3.80(m,2H),3.50-3.48(m,2H),3.49(s,3H),3.45(s,3H),3.41-3.28(m,1H),3.08-2.95(m,1H),2.22(s,3H),2.11(s,3H),1.30-1.27(m,3H))。
example 2: preparation of Compound B-1
Compound C-1(28g, 40.36mmol) was dissolved in dichloromethane (600mL) at room temperature, dess-martin oxidant (51.35g, 121.08mmol) was added, the mixture was stirred at room temperature for 0.5 h, and TLC monitored for completion of the starting material reaction. The reaction mixture was diluted with ether (600mL), filtered, and the filtrate was washed with a saturated sodium bicarbonate solution (150mL) and a saturated brine (150mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound B-1(26.52g, yield: 95%,1H-NMR(400MHz，CDCl3)：9.03(d,0.5H),8.84(d,0.5H),6.69-6.66(s,1H),6.23(d,1H),6.08-5.90(m,1H),5.88(s,1H),6.01-5.82(m,1H),5.78(s,1H),5.75-5.56(d,1H),5.45-4.50(m,10H),4.46-4.00(m,6H),3.71-3.73(s,3H),3.42-3.40(s,3H),3.18-3.06(m,1H),2.62-2.52(m,1H),2.22(s,3H),2.02(s,3H),1.21-1.18(m,3H))。
example 3: preparation of Compound A-1
Compound B-1(26g, 37.58mmol) was added to a three-necked flask at room temperature, argon was replaced, trifluoroacetic acid/dichloromethane (1.7L, v/v ═ 1/200 where trifluoroacetic acid was 112.74mmol) was added, and the reaction was stirred at room temperature until TLC monitored complete; the reaction solution was diluted with dichloromethane (3L), washed with saturated sodium bicarbonate solution (1L) and saturated sodium chloride (1L) in this order, dried over anhydrous sodium sulfate, filtered with suction, concentrated, separated by column chromatography (EA/PE ═ 1/5), and concentrated to give off-white solid compound a-1(23.12g, yield: 95%,1H-NMR(400MHz，CDCl3)：9.63-9.57(d,1H),6.76(s,1H),6.30-6.08(m,1H),6.10-5.10(m,9H)4.89-3.86(m,9H),3.82(s,3H),3.69-3.60(m,1H),3.28-3.12(m,2H),2.77(dd,J＝17.7,8.1Hz,1H),2.08(s,3H),1.52(s,3H),1.24(t,3H))。
example 4: preparation of Compound E-1
Methanol (7.2ml, 177.5mmol) was dissolved in tetrahydrofuran (144ml) and prepared ready for use. Dissolving compound A-1(23g, 35.5mmol) in tetrahydrofuran (230mL), replacing with argon for three times, cooling to 0 ℃, adding lithium borohydride (3.87g, 177.5mmol) in one portion, adding the prepared methanol/tetrahydrofuran mixed solvent in ten portions under the protection of argon, keeping the temperature of the system not higher than 10 ℃, continuing to stir for 1 hour after the addition is finished, keeping the reaction temperature not higher than 10 ℃, detecting that the reaction is complete, detecting that no cyano reduction by-product is detected, diluting the reaction solution with ethyl acetate (400mL), washing with 0.1N diluted hydrochloric acid (250mL), extracting the aqueous phase with ethyl acetate (150mLx2), combining the organic phases, washing with saturated aqueous sodium bicarbonate solution (150mL) and saturated sodium chloride (150mL), drying with anhydrous sodium sulfate, filtering, concentrating, purifying by column chromatography (EA: PE ═ 1:9-1:3), concentration and drying gave compound E-1 as a white solid (20.64g, yield: 96%, characterization information of compound E-1 was in agreement with literature reports).
Example 5: preparation of Compound C-2
Compound D-2(10g, 11.27mmol) was dissolved in tetrahydrofuran (250mL), and hydropyridine fluoride (5.58g, 56.35mmol) was added to prepare compound C-2(8.45g, yield: 92%, LC-MS: M/z 815.95(M + H) as an oil according to the method described in example 1+)。
Example 6: preparation of Compound B-2
Compound C-2(2g, 2.45mmol) was dissolved in tetrahydrofuran (30ml), 2-iodoxybenzoic acid (686mg, 2.45mmol) was added, and Compound B-2 (1) was prepared as an oil according to the procedure described in example 279g, yield: 90%, LC-MS: M/z 814.13(M + H)+)。
Example 7: preparation of Compound A-2
Using compound B-2(1g, 1.23mmol), p-toluenesulfonic acid/acetonitrile (992ml, v/v ═ 1/500, where p-toluenesulfonic acid was 12.3mmol), according to the method described in example 3, compound A-2(851mg, yield: 90%, LC-MS: M/z 769.68(M + H) was prepared as an off-white solid+)。
Example 8: preparation of Compound E-2
Compound A-2(500mg, 0.65mmol) was dissolved in tetrahydrofuran (2.6ml), cooled to 0 ℃ under an argon atmosphere, lithium borohydride (141mg, 6.5mmol) was added in one portion, while maintaining the system temperature at not more than 10 ℃, and a mixed solvent of methanol/acetonitrile (13 mmol of methanol dissolved in acetonitrile 20ml) was added in 5 portions to prepare compound E-2(448mg, yield: 93%, LC-MS: M/z 741.77(M + H) as a white solid according to the method described in example 4+)。
Example 9: preparation of Compound C-3
Compound D-3(1g, 1.04mmol) was dissolved in acetonitrile/tetrahydrofuran (30ml, v/v ═ 2/1), HF (50% aqueous solution, 20.8mmol, 0.832g) was added dropwise, and according to the procedure shown in example 1, compound C-3(817mg, yield: 93%, LC-MS: M/z 846.05(M + H) was prepared as an oil+)。
Example 10: preparation of Compound B-3
Compound C-3(817mg, 0.966mmol) was dissolved in methylene chloride (20ml), and dess-Martin oxidant (2.05g, 4.83mmol) was added to prepare compound B-3(757mg, yield: 93%, LC-MS: M/z 844.13(M + H) as an oil according to the procedure shown in example 2+)。
Example 11: preparation of Compound A-3
Using compound B-3(500mg, 0.59mmol), trifluoroacetic acid/acetonitrile/dichloromethane (22ml, 1/50/50 wherein trifluoroacetic acid is 2.95mmol), compound A-3 was prepared as an off-white solid according to the procedure shown in example 3(357mg, yield: 85%, LC-MS: M/z 713.75(M + H)+)。
Example 12: preparation of Compound E-3
Compound A-3(200mg, 0.28mmol) was dissolved in acetonitrile (2.8ml), sodium borohydride (10mg, 0.28mmol) was added in one portion while maintaining the reaction system at not more than 10 ℃ under nitrogen, and a methanol/tetrahydrofuran mixed solvent (0.4ml, v/v. RTM. 1/10, wherein methanol is 0.84 mmol) was added in 2 portions to prepare compound E-3(169mg, yield: 90%, LC-MS: M/z 671.73(M + H)) as a white solid according to the procedure described in example 4+)。
Example 13: preparation of Compound C-4
Compound D-4(10g, 12.1mmol) was dissolved in an acetonitrile/dichloromethane mixed solvent (300mL, v/v ═ 2:1), triethylamine trihydrofluoride (19.5g, 121mmol) was added, and according to the method described in example 1, Compound C-4(7.81g, yield: 91%, LC-MS: M/z 710.58(M + H) was prepared as an oil+)。
Example 14: preparation of Compound B-4
Compound C-4(7.81g, 11mmol) was dissolved in a dichloromethane/tetrahydrofuran mixed solvent (200ml, v/v ═ 1:1), dess-martin (9.33g, 22mmol) was added, and according to the procedure described in example 2, Compound B-4(7.08g, yield: 91%, LC-MS: M/z 708.57(M + H) was prepared as an oil+)。
Example 15: preparation of Compound A-4
Compound B-4(7.08g, 10mmol), trifluoroacetic acid/tetrahydrofuran/dichloromethane (903ml, v/v/v ═ was used
1/100/200 in which trifluoroacetic acid was 40mmol) was prepared according to the procedure shown in example 3 to give compound a-4(5.84g, yield: 88%, LC-MS: M/z 664.51(M + H)+)。
Example 16: preparation of Compound E-4
Compound a-4(5.8g, 8.74mmol) was dissolved in THF/dichloromethane (87ml, v/v ═ 1:1), under nitrogen protection, lithium borohydride (761mg, 34.96mmol) was added in one portion, maintaining the reaction system at no more than 10 ℃, and a methanol/acetonitrile/tetrahydrofuran mixed solvent (110ml, v/v/v ═ 1/15/15 where methanol was 87.4mmol) was added in eight portions, and compound E-4(4.94g, yield: 91%, LC-MS: M/z 622.48(M + H) was prepared as a white solid according to the method described in example 4+)。
Example 17: preparation of Compound C-5
Compound D-5(1g, 1.37mmol) was dissolved in acetonitrile/tetrahydrofuran solventTo (30mL, v/v ═ 1:2) was added pyridine hydrogen fluoride (2.03g, 20.55mmol), and according to the procedure described for example 1, compound C-5 was prepared (835mg, yield: 93%, LC-MS: M/z 656.58(M + H)+)。
Example 18: preparation of Compound B-5
Compound C-5(830mg, 1.26mmol) was dissolved in methylene chloride (20ml), and 2-iodoxybenzoic acid (353mg, 1.26mmol) was added to prepare compound B-5(758mg, yield: 92%, LC-MS: M/z 654.52(M + H) according to the method of example 2+)。
Example 19: preparation of Compound A-5
Using compound B-5(745mg, 1.14mmol), trifluoroacetic acid/dichloromethane/tetrahydrofuran (86ml, v/v/v ═ 1/30/70 wherein trifluoroacetic acid was 11.4mmol), the procedure shown in example 3 was carried out to give compound A-5(567mg, yield: 88%, LC-MS: M/z 566.51(M + H) as an off-white solid+)。
Example 20: preparation of Compound E-5
Compound A-5(565mg, 1mmol) was dissolved in THF (10ml) under argon protection, sodium borohydride (76mg, 2mmol) was added in one portion while maintaining the reaction at no more than 10 deg.C, and a mixed solvent of methanol/tetrahydrofuran (9.6ml, v/v ═ 1/15 where methanol was 15mmol) was added in seven portions to afford compound E-4(494mg, yield: 92%, LC-MS: M/z 538.51(M + H) as a white solid prepared according to the method described in example 4+)。
Example 21: preparation of Compound C-6
Compound D-6(3.1g, 4.2mmol) was dissolved in acetonitrile (50mL), and pyridine hydrogen fluoride (6.25g, 63mmol) was added to prepare compound C-6(2.51g, yield: 96%, LC-MS: M/z 624.59(M + H) as an oil according to the method described in example 1+)。
Example 22: preparation of Compound B-6
Compound C-6(2.5g, 4mmol) was dissolved in methylene chloride (60ml), and dess-Martin oxidant (5.09g, 12mmol) was added to prepare compound B-6(2.36g, yield: 95%, LC-MS: M/z622.56(M + H) as an oil according to the procedure described in example 2+)。
Example 23: preparation of Compound A-6
Using compound B-6(2.3g, 3.7mmol), trifluoroacetic acid/dichloromethane (170ml, 11.1mmol as trifluoroacetic acid, v/v ═ 1/200, according to the procedure shown in example 3, Compound A-6 was prepared as an off-white solid (2.03g, yield: 95%, LC-MS: M/z 578.52(M + H)+)。
Example 24: preparation of Compound E-6
Compound A-6(2.02g, 3.5mmol) was dissolved in THF (35ml) under argon protection and sodium borohydride (662mg, 17.5mmol) was added in one portion, maintaining the reaction at no more than 10 deg.C, and methanol/tetrahydrofuran mixed solvent (36.8ml, v/v ═ 1/25 where methanol was 35mmol) was added in four portions to afford compound E-6(1.76g, yield: 94%, LC-MS: M/z 536.51(M + H) as a white solid prepared according to the method described in example 4+)。
Comparative example 1: preparation of Compound F
Dissolving compound D-1(30g, 37.1mmol) in tetrahydrofuran (240mL) at room temperature, replacing with argon three times, cooling to 0 ℃, adding lithium borohydride solid (4.08g, 185.8mmol) in one step, slowly adding methanol (7.5mL) dropwise under the protection of argon, keeping the temperature at 0 ℃ and continuing stirring for 10 hours, diluting the reaction solution with ethyl acetate, washing with 0.1N diluted hydrochloric acid, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with saturated aqueous sodium bicarbonate solution and saturated sodium chloride in turn, drying with anhydrous sodium sulfate, filtering, concentrating, purifying by column chromatography (EA: PE 1:9-1:3), concentrating and drying to obtain compound F (5.68g, yield 20%, and the characteristic information of the compound F is consistent with the literature report).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (6)
1. A synthetic method of a Trapentine intermediate E is characterized by comprising the following steps:
step 1: and (3) preparing a compound C from the compound D in an organic solvent at room temperature under the action of a deprotection reagent:
step 2: oxidizing the compound C under the action of an oxidizing agent at room temperature to obtain a compound B:
and step 3: and (2) preparing the compound B in an organic solvent at room temperature under the protection of inert gas to obtain a compound A:
and 4, step 4: under the protection of inert gas, dissolving the compound A in a second organic solvent, adding a reducing agent, adding the mixture of methanol and a first organic solvent in batches, and reacting to obtain the compound E, wherein the first organic solvent and the second organic solvent are respectively and independently selected from tetrahydrofuran, acetonitrile, dichloromethane, toluene or any combination thereof;
wherein R is1、R2Each independently selected from hydrogen, methyl, ethyl, OR OR1、OR2Taken together to form-OCH2O-；
R3Selected from methyl and ethyl;
R4selected from the group consisting of methyl, ethyl, allyloxycarbonyl, allyl, and 2,2, 2-trichloroethoxycarbonyl;
R5selected from methyl, ethyl, allyloxycarbonyl, allyl, 2,2, 2-trichloroethoxycarbonyl;
R1' and R2' Each is independently selected from straight or branched C1-6Alkyl radical, C1-6Alkoxy-substituted C1-6Alkoxy radical C1-6Alkyl, OR OR1’、OR2' Co-constituent-OCH2O-；
With the proviso that when R1' or R2Is' as a quilt C1-6Alkoxy-substituted C1-6Alkoxy radical C1-6When alkyl, the corresponding R1Or R2Is H; when R is1' or R2' is straight-chain or branched C1-6Alkyl OR OR1’、OR2' Co-constituent-OCH2When O is-O, R1' or R2' respectively with R1Or R2The same;
R6selected from the group consisting of methoxymethyl, 1-ethoxyethyl, and 2- (trimethylsilyl) ethoxymethyl;
R7selected from trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl.
2. The method of synthesis of claim 1, wherein compound a is
3. The synthetic method of claim 1 or 2 wherein in step 1, the deprotecting reagent is selected from the group consisting of aqueous hydrogen fluoride, pyridine hydrogen fluoride and triethylamine trihydrofluoride; the feeding molar ratio of the deprotection reagent to the compound D is 5-20: 1; the organic solvent is selected from acetonitrile, tetrahydrofuran, dichloromethane or any combination thereof.
4. The method of synthesis according to claim 1 or 2, wherein in step 2, the oxidant is selected from dess-martin oxidant and 2-iodoxybenzoic acid; the feeding molar ratio of the oxidant to the compound C is 1-5: 1; in step 3 a reaction solvent is used which is dichloromethane, tetrahydrofuran, toluene, acetonitrile or any combination thereof.
5. The synthesis process according to claim 1 or 2, wherein in step 3, the acid is selected from trifluoroacetic acid, sulfuric acid, hydrochloric acid, acetic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid; using an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofuran, toluene, or any combination thereof in step 3; the feeding molar ratio of the acid to the compound B is 3-10: 1; the volume ratio of the acid to the organic solvent is 1: 100-500.
6. The method of synthesis according to claim 1 or 2, wherein in step 4, the reducing agent is selected from lithium borohydride, sodium borohydride and lithium aluminum hydride; the feeding molar ratio of the reducing agent to the compound A is 1-10: 1; the volume ratio of the first organic solvent to the methanol is 10-40: 1; the feeding molar ratio of the methanol to the compound A is 3-20: 1; the molar concentration of the compound A in the second organic solvent is 0.1-0.25 mol/L; the addition batches of methanol/first organic solvent are selected from 2-10 times, the addition time interval between batches is not less than 10 minutes, and the reaction temperature is not more than 10 ℃.
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