CN106674330B - Preparation method of 34-Dimethyl apratoxin A/E - Google Patents
Preparation method of 34-Dimethyl apratoxin A/E Download PDFInfo
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Abstract
The invention belongs to the field of medicine, and relates to a preparation method of a compound 34-Dimethyl apraxin A/E with extremely strong antitumor activity, which takes pivalaldehyde as an initial raw material, synthesizes key long-chain fatty acid fragments through 9 steps of reaction, and synthesizes a target compound through 16 steps of linear steps.
Description
Technical Field
The invention belongs to the field of medicines, relates to a new synthesis route of 34-Dimethyl apraxin A/E, and particularly relates to a preparation method of a compound 34-Dimethyl apraxin A/E with extremely strong antitumor activity.
Background
The prior art discloses that 34-Dimethyl apratoxin A/E is an active compound (J Med Chem,2014,57:3011-50The value was 1.99 nM.
The only synthetic route currently disclosed for 34-Dimethyl apraxin A/E includes: the target compound is obtained by condensing a tripeptide fragment, a 4-amino-5-mercaptopentanoic acid fragment and a 7-proline long-chain fatty acid and finally performing macrocyclic lactamization; for the synthesis of 7-proline long-chain fatty acid fragments, the synthetic route adopts pivalaldehyde as a raw material, and the fragments are obtained by 19 steps of asymmetric aldol condensation, tert-butyl dimethyl silicon base protection, reduction, hydroxyl activation elimination, tert-butyl dimethyl silicon base removal, esterification, olefin double decomposition cyclization, asymmetric 1, 4-addition, amine ester exchange, p-methoxybenzyl protection, reduction, aldol condensation, hydrolysis, allyl ester protection, trichloroethoxycarbonyl protection, p-methoxybenzyl removal, esterification and allyl ester removal with the yield of 12%; for the synthesis of the 4-amino-5-mercaptopentanoic acid fragment, the synthesis route takes (D) -cysteine as a raw material, and the synthesis of the 4-amino-5-mercaptopentanoic acid fragment is completed by 6 steps of reactions including amidation, reduction, wittig reaction, reduction, hydrolysis and nucleophilic substitution with the yield of 24%; the tripeptide fragment of the synthetic route is obtained by amidating sequentially from N end to C end; after the synthesis of three fragments is completed, the synthesis route starts from 7-proline long-chain fatty acid fragments to assemble the fragments, and the synthesis of a target product is completed through amidation, cyclization, trichloroethoxycarbonyl, allyl ester removal, amidation, allyl removal, fluorenylmethoxycarbonyl removal and macrocyclic lactamization (J Med Chem,2014,57: 3011-; the synthetic route has the following problems:
1. the reaction steps of the whole route are too long, and a large number of protecting groups are used for reacting with deprotection groups, so that the total yield of target products is low;
2. the reaction for synthesizing the intermediate 8 uses a Grubbs catalyst which is expensive, so that the synthesis cost is high;
3. the reaction for synthesizing the intermediate 9 uses a virulent cyaniding reagent, so that the whole synthesis route is not environment-friendly;
4. the specific implementation substrate feeding amount of the synthetic route is small, and the yield cannot be guaranteed after the reaction amplification.
All of the above problems will cause difficulty in mass production of 34-Dimethyl apratoxin A/E (compound 31).
Reaction conditions are as follows: d-Proline, Acetone; tbscl, imidazole; NaBH4；IV.MsCl；V.t-BuOK；VI.TBAF；VII.
VIII.Grubbs G2；IX.MeLi，CuCN；X.
Al(Me)3XI.PMBOC(NH)CCl3；XII.DIBAL-H；XIII.
D-(N-Ts)-Val，BH3；XIV，LiOH；XV，AllylBr；XVI，TrocCl；XVII，DDQ；XVIII，Fmoc-Pro-OH，Cl3PhCOCl；XIX，Pd(PPh3)4 
Reaction conditions are as follows: I.
EDCl，HOBt；II.LiAlH4，III.
IV，NaBH4，V，LiOH；VI.AllylBr
reaction conditions are as follows: i.25, TMSOTf, lutidine, PyAOP II.TiCl4；III.Zn，NH4OAc；IV.Pd(PPh3)4
Reaction conditions are as follows: et2NH；II.PyAOP；Et2NH III.Pd(PPh3)4；IV.Pd(PPh3)4。
Disclosure of Invention
The invention aims to overcome the defects of the reported synthetic route in the prior art, provide a synthetic route for efficiently preparing 34-Dimethyl apraxin A/E and carry out scale preparation.
Specifically, the invention provides a preparation method of 34-Dimethyl apratoxin A/E, which comprises the following synthetic route:
the method comprises the following steps:
(1) d-proline is used as a catalyst, pivalaldehyde is used as a starting material to perform an asymmetric aldol condensation reaction with acetone to generate (S) -4-hydroxy-5, 5-dimethylhex-2-one (1);
(2)1 in dry tetrahydrofuran, reacting with diisopropylaluminium hydride at-78 ℃ for 5-10 hours, and stereoselectively reducing the ketone carbonyl into hydroxyl to obtain (2S,4S) -5, 5-dimethylhexane-2, 4-diol (32);
(3) in the presence of an inorganic base (e.g. NaOH, KOH, CsOH, Ba (OH)2、Mg(OH)2、Ca(OH)2、Sr(OH)2、KHCO3、K2CO3、Na2CO3、Cs2CO3) Or in the presence of organic base (such as triethylamine, tri-n-butylamine and pyridine), cyclizing the compound 32 and thionyl chloride to obtain (4S,6S) -4-tert-butyl-6-methyl propylene sulfite, and oxidizing allyl sulfite into allyl sulfate by using ruthenium trichloride sodium periodate to obtain (4S,6S) -4- (tert-butyl) -6-methyl propylene sulfate (33);
(4)33 and allyl copper magnesium reagent to generate bisulfate through nucleophilic substitution reaction, and then hydrolyzing under acidic condition (such as sulfuric acid and hydrochloric acid) to generate (3S,5S) -2,2, 5-trimethyl octyl-7-en-3-ol (34);
(5) carrying out esterification reaction on 34 and Fmoc-L-proline under the condition of 2,4, 6-trichlorobenzoyl chloride to obtain olefin 35;
(6)35 carbon-carbon double bonds are oxidized with ozone at-78 ℃ to form ozonides, which are then reduced with reducing agents (e.g. dimethyl sulfide, triphenylphosphine) to the aldehydes (36);
(7) aldehyde 36 and 1-methoxy-2-methyl-1- (trimethylsiloxy) propylene are subjected to asymmetric aldol condensation reaction at-78 ℃ under the catalysis of Lewis acid formed by N-Ts-D-Val and borane to generate methyl ester (37);
(8)37 hydrolyzing the methyl ester to carboxylic acid under acidic condition, more specifically, 37 reacting in the presence of inorganic acid (such as sulfuric acid, hydrochloric acid) and high boiling point solvent (such as DMF, DMSO, dioxane, toluene, pyrrolidone) at 20-160 deg.C for 0.5-10 hr to obtain carboxylic acid (38);
(9) condensation of N-Boc-S-Trt-D-cysteine with 2, 2-dimethyl-1, 3-dioxane-4, 6-dione in the presence of a condensing agent (e.g. DCC, EDC, HATU, PyAOP) gives the carbamate (39);
(10)39 is reduced into methylene by a sodium borohydride-acetic acid reduction system to obtain amino acid methyl ester (40);
(11) amino acid methyl ester 40 reacts in a high boiling point solvent (such as DMF, DMSO, dioxane, toluene and pyrrolidones) for 0.5 to 10 hours at the temperature of between 20 and 160 ℃ to carry out decarboxylation and cyclization, thus obtaining lactam (41);
(12)41 is hydrolyzed under basic conditions to (S) -4- ((tert-butoxycarbonyl) amino) -5- (triphenylmethylmercapto) pentanoic acid (24). More specifically 41 in an inorganic base (e.g. NaOH, KOH, CsOH, Ba (OH)2、Mg(OH)2、Ca(OH)2、Sr(OH)2、KHCO3、K2CO3、Na2CO3、Cs2CO3) Or in the presence of an organic base (such as triethylamine, pyridine), using lower alcohol (such as methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol) or other solvent (such as acetone, DMF, DMSO, THF, dioxane, pyrrolidones) as solvent, reacting for 0.5-10 hours at the temperature range of 20-160 ℃, and hydrolyzing to (S) -4- ((tert-butoxycarbonyl) amino) -5- (triphenylmethylmercapto) pentanoic acid (24);
(13)24 and allyl bromide under alkaline conditions to generate (S) -4- ((tert-butoxycarbonyl) amino) -5- (triphenylmethyl mercapto) pentanoic acid allyl ester (25) through nucleophilic substitution reaction;
(14)25 removing tert-butyloxycarbonyl under the conditions of trimethylsilyl trifluoromethanesulfonate and 2, 6-lutidine, and then condensing with carboxylic acid 38 under the condition of a condensing agent PyAOP to form amide 42;
(15)42 are cyclized by heating under the catalysis of a Lewis acid to form the thiazoline compound 27, more specifically, under the catalysis of a Lewis acid (such as TiCl)4、PCl5) In the presence of lower halogenated alkane as a solvent (such as dichloroethane and dibromoethane), reacting for 0.5 to 6 hours at the temperature of between 20 and 100 ℃ to form a thiazoline compound 27 through cyclization;
(16)27 removing allyl ester with palladium tetratriphenylphosphine to obtain carboxylic acid 28;
(17) compound 29 (see, e.g., J Med Chem,2014,57:3011-3029) is subjected to Fmoc-protecting group removal with an organic base (e.g., diethylamine) and then subjected to condensation reaction with carboxylic acid 28 in the presence of a condensing agent (e.g., HATU, PyAOP) to obtain allyl ester 30;
(18)30 removing allyl ester with palladium tetratriphenylphosphine, removing Fmoc protecting group with diethylamine, and performing intramolecular amidation reaction at room temperature for 10-24 hr at 1nM concentration of condensing agent (such as HATU, PyAOP) in dichloromethane solvent to obtain 34-Dimethyl apraxin A/E.
In the present invention, the steps in the synthetic route to compounds 35, 37, 38, 27 and 34-Dimethyl apraxin A/E are key reaction steps.
In the invention, the specific reaction conditions are as follows:
Reaction conditions are as follows: I.
DCC，DMAP；II.NaBH4，AcOH，III.Tol；IV，NaOH；V，AllylBr
reaction conditions are as follows: i.25, TMSOTf, lutidine,38，PyAOP II.TiCl4；III.Pd(PPh3)4
reaction conditions are as follows: et2NH；II.PyAOP；Et2NH III.Pd(PPh3)4；IV.Pd(PPh3)4。
The invention has the advantages that:
1. the invention takes pivalaldehyde as an initial raw material, synthesizes key long-chain fatty acid fragments through 9 steps of reaction, synthesizes target compounds through 16 steps of linear steps, saves 9 steps of reaction, has simpler and more convenient preparation method and obviously shortens the synthesis route compared with the prior art.
2. The 9-step reaction is saved, so that the product quality and yield are improved, and the method is suitable for large-scale preparation.
3. Compared with the existing synthetic route, the reaction used in the invention does not use expensive and highly toxic reagents, so that the whole preparation method is more green and economic.
The invention is further illustrated but is not to be construed as being limited by the following examples.
The starting materials and reagents used in the following reactions were supplied by Shanghai Tantake technology, Inc.
Detailed Description
EXAMPLE 1 preparation of (S) -4-hydroxy-5, 5-dimethylhex-2-one (1)
D-proline (15.9g, 138.1mmol) was weighed and added to a mixed solution of 960mL DMSO and 240mL acetone, and stirred at normal temperature for half an hour, pivalaldehyde (50mL, 460.4mmol) was added to the above system, stirred at room temperature for 7 days, and saturated ammonium chloride solution (500mL) was added under ice bath to quench the reaction, extracted with ethyl acetate (400mL × 3), the organic phase was washed with saturated saline (400mL × 2), dried with anhydrous sodium sulfate, concentrated to dryness, and subjected to column chromatography with petroleum ether/ethyl acetate ratio of 6:1 to obtain a pale yellow oily liquid 52(39.8g, 60.0%).
MS(API-ES)：145.2[M+H]+，127.2[M-H2O+H]+。
1H NMR(400MHz，CDCl3)：3.68(d，J＝10.5Hz，1H)，2.42-2.61(m，2H)，2.01(s，3H)，0.87(s,9H)。
EXAMPLE 2 preparation of (2S,4S) -5, 5-dimethylhexane-2, 4-diol (32)
Dissolving 1(38.0g,263.7mmol) in tetrahydrofuran (300mL), cooling the solution to-78 ℃, dropwise adding DIBAL-H (263.7mL,395.5mmol,1.5M toluene solution), reacting at-78 ℃ for 5 hours after dropwise adding, dropwise adding 1M hydrochloric acid (200mL) to quench the reaction, filtering the reaction system with kieselguhr, concentrating the filtrate to remove toluene and tetrahydrofuran, dissolving with ethyl acetate (1L), washing with saturated common salt water, and drying with anhydrous sodium sulfate. Sodium sulfate was filtered off, the organic phase was concentrated to dryness and column chromatography on petroleum ether/ethyl acetate 6:1 afforded 32(24.8g, 65.3%) as a white solid.
MS(API-ES):169.2[M+Na]+。
1H NMR(400MHz,CDCl3):3.92(m,1H),3.54(dd,J＝13.6,1.3Hz,1H),3.28(m,2H),1.49(brd,J＝5.0Hz,1H),1.30(d,J＝5.0Hz,1H),1.14(d,J＝6.8Hz,3H),0.89(s,9H).。
EXAMPLE 3 preparation of (4S,6S) -4-tert-butyl-6-methylpropanesulfonic acid allyl ester (33)
32(66.5g,454.5mmol), anhydrous sodium carbonate (482.2g,4.5mol) and dry dichloromethane (500mL) were mixed, thionyl chloride (164.7mL,22.7mol) was added dropwise at-15 ℃ and the reaction was carried out at room temperature for 3 hours after completion of the addition. Filtering the reaction system by using diatomite, concentrating the filtrate to be dry, and directly using the filtrate for the next reaction without refining;
the crude product from the previous step was dissolved in a mixed solvent (water (460mL), acetonitrile (230mL), carbon tetrachloride (460mL)), and ruthenium trichloride (6.0g,23.0mmol) and sodium periodate (147.6g,690.0mmol) were added under ice-bath conditions to react at room temperature for 6 hours. Extraction with dichloromethane (400mL × 3), washing of the organic phase with saturated ammonium chloride solution, saturated sodium bicarbonate solution, saturated brine, drying of the organic phase over anhydrous sodium sulfate, filtration of sodium sulfate, concentration of the filtrate to dryness, and column chromatography with petroleum ether/ethyl acetate ═ 6:1 gave 33(68.4g, 71.5%) as a white solid.
MS(API-ES):231.1[M+Na]+。
1H NMR(400MHz,CDCl3):4.85-4.87(m,1H),4.64(dd,J＝11.2,7.2Hz,1H),1.85(t,J＝7.2,1H),1.72(t,J＝11.2,1H),1.47(d,J＝8.2Hz,3H),0.94(s,9H).。
EXAMPLE 4 preparation of (3S,5S) -2,2, 5-Trimethyloct-7-en-3-ol (34)
34 was mixed with cuprous iodide (38.1g,0.2mol) and dry tetrahydrofuran (200mL), allylmagnesium bromide (650mL,1M in ether) was added dropwise at-25 deg.C, 20% sulfuric acid (500mL) was added dropwise after 8 hours of reaction at 25 deg.C, and the reaction was carried out at room temperature for 10 hours after completion of the addition. Celite was filtered, the filtrate was separated, the aqueous phase was extracted with ether (200mL × 2), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the filtrate was concentrated to dryness, and column chromatography was performed with petroleum ether/ethyl acetate ═ 6:1 to give 33(24.0g, 88.1%) as a yellow oily liquid.
MS(API-ES):193.2[M+Na]+。
1H NMR(400MHz,CDCl3):5.81–5.91(m,1H),4.96–5.05(m,2H),3.56(dd,J＝10.2,1.8Hz,1H),2.33–2.40(m,1H),1.95–2.02(m,1H),1.82–1.93(m,1H),1.38-1.43(m,1H),1.16-1.21(m,1H),0.98(d,J＝6.6Hz,1H),0.90(s,9H).。
EXAMPLE preparation of 5 olefin (35)
Fmoc-proline (9.5g,28.2mmol) was mixed with dry tetrahydrofuran (30mL) and 2,4, 6-trichlorobenzoyl chloride (5.2mL,35.3mmol) and diisopropylethylamine (6.2mL,35.3mmol) were added dropwise at 0 deg.C and reacted for 10 min at 0 deg.C. A solution of 33(4.0g,23.5mmol) in 5mL of tetrahydrofuran was added dropwise and reacted at 0 ℃ for 30 minutes. Thereafter, dimethylaminopyridine (8.6g,70.5mmol) was added in one portion and reacted at room temperature for 6 hours. Ethyl acetate (500mL) was added for dilution, washed twice with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution and a saturated brine, respectively, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the filtrate was concentrated to dryness for column chromatography with petroleum ether/ethyl acetate 4:1 to give a pale yellow oily liquid 35(19.1g, 81.2%).
MS(API-ES):512.3[M+Na]+。
1H NMR(400MHz,CDCl3):7.73–7.85(m,2H),7.53–7.70(m,2H),7.36–7.46(m,2H),7.27–7.36(m,2H),5.58–5.82(m,1H),4.85–5.10(m,2H),4.23–4.58(m,4H),4.09–4.23(m,1H),3.63–3.74(m,1H),3.49–3.62(m,1H),2.38–1.92(m,3H),1.62–1.99(m,1H),1.51–1.65(m,1H),1.31–1.50(m,3H),0.79–0.11(m,13H).。
EXAMPLE 6 preparation of aldehyde (36)
Dissolving 35(12.0g,24.5mmol) in dry dichloromethane (200mL), introducing ozone into the reaction system at-78 ℃ until the reaction system turns blue, introducing nitrogen into the reaction system until the blue color fades, dropwise adding dimethyl sulfide (7.2mL,98.1mmol) into the reaction system, and slowly raising the temperature of the reaction system to room temperature for reaction for 12 hours. The reaction was concentrated to dryness and column chromatography was performed with petroleum ether/ethyl acetate 4:1 to give 35(9.1g, 75.6%) as a pale yellow oily liquid.
EXAMPLE 7 preparation of methyl ester (37)
N-Ts-valine (30.0g,106.9mmol) was dissolved in dry dichloromethane (600mL), and 1M borane in tetrahydrofuran (106.9mL,106.9mmol) was added dropwise at 0 ℃ and reacted for 2 hours at 0 ℃. The reaction system was cooled to-78 ℃ and a solution of aldehyde 37(35.0g,71.2mmol) in 400mL of dry methylene chloride was added dropwise, followed by addition of 1-methoxy-2-methyl-1- (trimethylsiloxy) propene dropwise and reaction at-78 ℃ for 5 hours. With Na having a pH of 82HPO4And NaH2PO4The reaction was quenched with the buffer solution (100mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off sodium sulfate and concentrated to dryness, and column chromatography was performed with petroleum ether/ethyl acetate 4:1 to give 37(35.0g, 82.8%) as a white solid.
MS(API-ES):594.4[M+H]+。
EXAMPLE 8 preparation of carboxylic acid (38)
37(8.4g,14.2mmol) was dissolved in dioxane (100mL), concentrated hydrochloric acid (30.0mL,946.2mmol) was added, and the mixture was heated to 110 ℃ for reaction for 10 hours. The reaction was cooled to 0 ℃,1M NaOH solution was added to adjust pH 5, ethyl acetate was extracted (150mL × 3), the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, concentrated to dryness, and column chromatography was performed with petroleum ether/ethyl acetate 1:2 to obtain 38(6.3g, 76.3%) as a pale yellow solid.
MS(API-ES):580.3[M+H]+。
1H NMR(400MHz,CDCl3):7.76(d,J＝7.1Hz,2H),7.54–7.68(m,2H),7.36–7.43(m,2H),7.28–7.36(m,2H),4.91(d,J＝11.8Hz,1H),4.41–4.49(m,1H),4.23–4.38(m,1H),3.73–3.82(m,2H),3.58–3.73(m,4H),3.44–3.58(m,2H),2.22–2.36(m,1H),1.91–2.08(m,4H),1.57–1.85(m,7H),0.68–1.06(m,26H).。
EXAMPLE 9 preparation of carbamate (39)
N-Boc-S-Trt-D-cysteine (10.0g,21.6mmol) was dissolved in dry dichloromethane (200mL), 2-dimethyl-1, 3-dioxane-4, 6-dione (3.4g,23.7mmol), dicyclohexylcarbodiimide (4.9g,23.7mmol) and dimethylaminopyridine (4.0g,32.4mmol) were added sequentially at 0 ℃ and reacted at room temperature for 16 hours. Washing with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated saline solution, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, and concentrating the filtrate to dryness for direct use in the next reaction without refinement.
EXAMPLE 10 preparation of Carbamate (40)
The crude 39 from the previous step was dissolved in dry dichloromethane (50mL), glacial acetic acid (15.6mL,237.6mmol) was added at 0 ℃ and sodium borohydride (2.0g,54.0mmol) was added in portions and reacted at 0 ℃ for 1 hour. Dichloromethane (200mL) was added for dilution, washed with saturated sodium bicarbonate solution and saturated brine, respectively, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the filtrate was concentrated to dryness and used in the next reaction without purification.
EXAMPLE 11 preparation of lactam (41)
Dissolving the unrefined 40 in the previous step in toluene (200mL), reacting at 110 ℃ for 8 hours, and concentrating the reaction solution to dryness, wherein the reaction solution can be directly used for the next step without being refined.
EXAMPLE 12 preparation of (S) -4- ((tert-Butoxycarbonyl) amino) -5- (triphenylmethylmercapto) pentanoic acid (24)
The crude 41 was dissolved in acetone (or other solvent as described above) (200mL), and a 2M aqueous solution of sodium hydroxide (or other base as described above) (54.0mL,108.0mmol) was added to the solution to react at room temperature for 3 hours. The pH was adjusted to 4 with 2M hydrochloric acid, extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off sodium sulfate, and the filtrate was concentrated to dryness and used in the next reaction without purification.
EXAMPLE 13 preparation of allyl (S) -4- ((tert-butoxycarbonyl) amino) -5- (triphenylmethylmercapto) valerate (25)
Unrefined 24 was combined with anhydrous potassium carbonate (7.4g,53.9mmol) and dry DMF (200mL) and allyl bromide (3.2mL,36.8mmol) was added. After 5 hours reaction at room temperature, the reaction salt was poured into 1M hydrochloric acid at 0 ℃ and extracted with ethyl acetate (100 mL. times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, the filtrate was concentrated to dryness, and column chromatography was performed with petroleum ether/ethyl acetate 4:1 to give yellow oily liquid 25(7.2g, 62.7%).
MS(API-ES):554.2[M+Na]+。
1H NMR(400MHz,CDCl3):3.68(d,J＝10.5Hz,1H),2.42-2.61(m,2H),2.01(s,3H),0.87(s,9H)。
EXAMPLE preparation of 14 amide 42
25(2.0g,3.8mmol) was dissolved in dry dichloromethane (48mL), and 2, 6-lutidine (6.8mL,46.3mmol) and trimethylsilyl trifluoromethanesulfonate (8.4mL,23.8mmol) were added in this order at 0 ℃ to react at room temperature for 1 hour. The reaction was quenched by adding methanol (5mL) dropwise at 0 deg.C, washed with saturated sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the filtrate was concentrated to dryness and used in the next reaction without purification.
Carboxylic acid 38(1.7g,2.9mmol) was dissolved in dry tetrahydrofuran (25mL), and the crude non-purified 25-det-butoxycarbonyl product from the previous step, (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tri-1-pyrrolidinophosphonium hexafluorophosphate (2.4g,4.6mmol) and N, N-diisopropylethylamine (1.7mL,9.6mmol) were added in this order and reacted at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate (200mL), washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness. Column chromatography on 1:2 petroleum ether/ethyl acetate gave 42 as a pale yellow oil (1.5g, 52.1%).
MS(API-ES):1015.6[M+Na]+。
1H NMR(400MHz,CDCl3):3.68(d,J＝10.5Hz,1H),2.42-2.61(m,2H),2.01(s,3H),0.87(s,9H)。
EXAMPLE 15 preparation of thiazoline Compound 27
42(2.3g,2.3mmol) was dissolved in dichloroethane (400mL), titanium tetrachloride (2.0mL,18.5mmol) was added, the reaction was allowed to react at 60 ℃ for 2 hours, the reaction was cooled to room temperature, and a saturated sodium bicarbonate solution (20mL) was added and stirred for 20 minutes. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the filtrate was concentrated to dryness. Column chromatography on petroleum ether/ethyl acetate 4:1 gave 27(0.8g, 47.5%) as a colorless oily liquid.
MS(API-ES):755.4[M+Na]+。
EXAMPLE 16 preparation of Carboxylic acid 28
27(0.65g,0.89mmol) was dissolved in dry tetrahydrofuran (10mL), and N-methylaniline (0.24mL,2.2mmol) and palladium tetrakistriphenylphosphine (104.0mg,0.09mmol) were added respectively to react at room temperature for 1 hour. The reaction solution was concentrated to dryness and subjected to column chromatography separation rapidly with petroleum ether/ethyl acetate 1:4 for the next reaction.
EXAMPLE 17 preparation of allyl ester 30
29 was dissolved in acetonitrile (10mL), and diethylamine (5mL) was added and reacted at room temperature for half an hour. The reaction was concentrated to dryness, azeotroped 3 times with toluene (5 mL. times.3), and dried under vacuum for 2 hours using an oil pump for the next reaction.
28 was dissolved in dry tetrahydrofuran (10mL), and the reaction product of the previous step, (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tri-1-pyrrolidinophosphonium hexafluorophosphate (1.1g,2.2mmol) and N, N-diisopropylethylamine (0.76mL,4.4mmol) were added in this order and reacted at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (200mL), washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness. Column chromatography on petroleum ether/ethyl acetate 1:4 gave white foamy solid 30(0.68g, 65.0%).
MS(API-ES):1144.6[M+Na]+。
1H NMR(400MHz,CDCl3):3.68(d,J＝10.5Hz,1H),2.42-2.61(m,2H),2.01(s,3H),0.87(s,9H)。
EXAMPLE 18 preparation of 34-Dimethyl apratoxin A/E
30(0.72g,0.64mmol) was dissolved in dry tetrahydrofuran (10mL), and N-methylaniline (0.17mL,1.6mmol) and palladium tetrakistriphenylphosphine (74.0mg,0.06mmol) were added respectively to react at room temperature for 1 hour. The reaction solution is concentrated to be dry, and the petroleum ether/ethyl acetate 1:4 is used as eluent for fast column chromatography separation and then used for the next reaction.
The reaction of the previous step was dissolved in acetonitrile (24mL), and diethylamine (12mL) was added and reacted at room temperature for half an hour. The reaction was concentrated to dryness, azeotroped 3 times with toluene (15 mL. times.3), and dried under vacuum for 2 hours using an oil pump for the next reaction.
The reaction of the previous step was dissolved in dry dichloromethane (740mL), and (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tri-1-pyrrolidinophosphonium hexafluorophosphate (0.85g,1.6mmol) and N, N-diisopropylethylamine (0.94mL,5.4mmol) were added in this order to react at room temperature for 24 hours. The reaction mixture was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness. Column chromatography on petroleum ether/ethyl acetate 1:4 gave 31(0.25g, 46.4%) as a white solid.
MS(API-ES):842.6[M+H]+。
Claims (14)
1. A preparation method of 34-Dimethyl apratoxin A/E is characterized by comprising the following steps:
(1): d-proline is used as a catalyst, pivalaldehyde is used as a starting material to perform an asymmetric aldol condensation reaction with acetone to generate (S) -4-hydroxy-5, 5-dimethylhex-2-one (a compound 1);
(2): stereoselective reduction of the ketocarbonyl group of compound 1 to a hydroxyl group with diisopropylaluminum hydride gives (2S,4S) -5, 5-dimethylhexane-2, 4-diol (compound 32);
(3): cyclizing the compound 32 and thionyl chloride under alkaline conditions to obtain (4S,6S) -4-tert-butyl-6-methyl propylene sulfite, and oxidizing allyl sulfite into allyl sulfate by using ruthenium trichloride sodium periodate to obtain (4S,6S) -4- (tert-butyl) -6-methyl propylene sulfate (a compound 33);
(4): carrying out nucleophilic substitution reaction on the compound 33 and an allyl copper magnesium reagent to generate bisulfate, and hydrolyzing under acidic conditions to generate (3S,5S) -2,2, 5-trimethyloct-7-en-3-ol (compound 34);
(5): under the condition of 2,4, 6-trichlorobenzoyl chloride, the compound 34 and Fmoc-L-proline are subjected to esterification reaction to obtain a compound 35;
(6): the compound 35 is oxidized by carbon-carbon double bond with ozone to form ozonide, and then reduced to compound 36 with reducing agent;
(7): the compound 36 and 1-methoxy-2-methyl-1- (trimethylsiloxy) propylene are subjected to asymmetric aldol condensation reaction under the catalysis of Lewis acid formed by N-Ts-D-Val and borane to generate a compound 37;
(8): compound 37 hydrolyzes the methyl ester under acidic conditions to compound 38;
(9): in the presence of a condensing agent, condensing N-Boc-S-Trt-D-cysteine and 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone to obtain a compound 39;
(10): reducing the ketone carbonyl of the compound 39 into methylene by using a sodium borohydride-acetic acid reduction system to obtain a compound 40;
(11): decarboxylation and cyclization of the compound 40 to obtain a compound 41;
(12): hydrolysis of compound 41 to (S) -4- ((tert-butoxycarbonyl) amino) -5- (triphenylmethylmercapto) pentanoic acid (compound 24) under basic conditions;
(13): carrying out nucleophilic substitution reaction on the compound 24 and allyl bromide under alkaline conditions to generate a compound 25;
(14): removing tert-butyloxycarbonyl from the compound 25 under the conditions of trimethylsilyl trifluoromethanesulfonate and 2, 6-lutidine, and then condensing with a compound 38 to form a compound 42;
(15): heating compound 42 under Lewis acid catalysis for cyclization to form compound 27;
(16): compound 27 is allyl ester removed with palladium tetratriphenylphosphine to give compound 28;
(17): removing Fmoc protecting group from the compound 29 by using organic base, and condensing with the compound 28 to obtain a compound 30;
(18): removing allyl ester from the compound 30 by using palladium tetratriphenylphosphine, removing Fmoc protecting group by using diethylamine, and then performing intramolecular amidation reaction to obtain 34-Dimethyl apraxin A/E;
the reaction formula is as follows:
2. the method according to claim 1, wherein the alkaline condition in the step (3) is that an inorganic base Na is adopted2CO3。
3. The method of claim 1, wherein the esterification with N-Fmoc-proline in step (5) is carried out using 2,4, 6-trichlorobenzoyl chloride as a catalyst.
4. The method according to claim 1, wherein ozone is used as an oxidizing agent and dimethyl sulfide is used as a reducing agent in the step (6).
5. The method according to claim 1, wherein the stereoselective reduction in step (2) is carried out at-78 ℃; the oxidation in the step (6) is carried out at-78 ℃; the asymmetric aldol condensation reaction in the step (7) is carried out at-78 ℃;
6. the method as claimed in claim 1, wherein the step (8) is carried out by hydrolysis under acidic conditions, and inorganic acids such as sulfuric acid and hydrochloric acid are used.
7. The process of claim 1, wherein step (8) is carried out under acidic conditions and the reaction solvent is dioxane.
8. The process according to claim 1, wherein the step (8) is carried out under acidic conditions at a reaction temperature of 110 ℃ to 160 ℃.
9. The process according to claim 1, wherein the step (8) is carried out in an acidic condition for 10 hours.
10. The process of claim 1, wherein the step (15) comprises cyclizing under acidic conditions using a Lewis acid such as TiCl4。
11. The process according to claim 1, wherein the step (15) is performed by cyclization under acidic conditions at a temperature of 60 ℃.
12. The process of claim 1, wherein step (15) is performed by cyclization under acidic conditions for a period of 2 hours.
13. The method according to claim 1, wherein the organic base in step (17) is diethylamine.
14. The process according to claim 1, wherein the intramolecular amidation reaction in step (18) is performed in a dichloromethane solvent.
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