CN113214335A - Lipid X intermediate and preparation method thereof - Google Patents
Lipid X intermediate and preparation method thereof Download PDFInfo
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- CN113214335A CN113214335A CN202010071520.7A CN202010071520A CN113214335A CN 113214335 A CN113214335 A CN 113214335A CN 202010071520 A CN202010071520 A CN 202010071520A CN 113214335 A CN113214335 A CN 113214335A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- HEHQDWUWJVPREQ-XQJZMFRCSA-N lipid X Chemical compound CCCCCCCCCCC[C@@H](O)CC(=O)N[C@H]1[C@@H](OP(O)(O)=O)O[C@H](CO)[C@@H](O)[C@@H]1OC(=O)C[C@H](O)CCCCCCCCCCC HEHQDWUWJVPREQ-XQJZMFRCSA-N 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 239000003960 organic solvent Substances 0.000 claims abstract description 41
- 238000006482 condensation reaction Methods 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 89
- 238000006243 chemical reaction Methods 0.000 claims description 68
- 239000002904 solvent Substances 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 15
- 229910052744 lithium Inorganic materials 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052698 phosphorus Inorganic materials 0.000 claims description 12
- 239000011574 phosphorus Substances 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 8
- DUWXVMIEMVFNGD-UHFFFAOYSA-N 2-(dimethoxymethyl)naphthalene Chemical compound C1=CC=CC2=CC(C(OC)OC)=CC=C21 DUWXVMIEMVFNGD-UHFFFAOYSA-N 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- -1 dimethyl-tert-hexylsilyl Chemical group 0.000 claims description 8
- 150000008282 halocarbons Chemical group 0.000 claims description 8
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 230000001681 protective effect Effects 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical group C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000002825 nitriles Chemical group 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000002091 cationic group Chemical group 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- QHXPOTVGOJSXCV-OAQYLSRUSA-N CCCCCCCCCCC[C@H](CC(O)=O)OC1=CC=CC2=CC=CC=C12 Chemical compound CCCCCCCCCCC[C@H](CC(O)=O)OC1=CC=CC2=CC=CC=C12 QHXPOTVGOJSXCV-OAQYLSRUSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000272459 Silybum marianum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a Lipid X intermediate and a preparation method thereof. The invention specifically provides a preparation method of a compound shown as a formula 5, which comprises the following steps: in an organic solvent, in the presence of alkali and a condensing agent, a compound shown as a formula 3 and a compound shown as a formula 4 are subjected to a condensation reaction shown as follows. The Lipid X intermediate disclosed by the invention is novel in structure, and the yield of the product synthesized by taking the Lipid X intermediate as a raw material is higher.
Description
Technical Field
The invention relates to a Lipid X intermediate and a preparation method thereof.
Background
Lipid X (shown below) is a precursor of lipopolysaccharide of gram-negative bacteria, and has antibacterial effect. 2-deoxy-1-oxy- (1, 1-dimethylethyl) dimethylsilyl-4, 6-oxy- [ -naphthylmethylene ] -2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino- β -D-glucopyranoside (shown below) is a key intermediate for the synthesis of Lipid X. At present, a synthetic route of the intermediate is not available, and only a few synthetic routes of compounds with similar structures are available, for example, Boons et al (WO 2012/135049A 1) synthesize 2-deoxy-1-oxo- [ dimethyl (1,1, 2-trimethylpropyl) silybum marianum ] -4, 6-benzylidene-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-alpha-D-glucopyranoside by six steps with D-glucose as a raw material, the reaction time of the route is long, most steps need to be purified by column chromatography, and the industrial production of the intermediate is limited. Miyamoto et al (Tetrahedron Letters,1992,33(26): 3725-. The method has the advantages of short route, simple operation and high yield.
Disclosure of Invention
The invention aims to overcome the defect of single synthetic route of the conventional Lipid X and provides a Lipid X intermediate and a preparation method thereof. The Lipid X intermediate disclosed by the invention is novel in structure, and the yield of the product synthesized by taking the Lipid X intermediate as a raw material is higher.
The present invention solves the above technical problems by the following means.
The invention provides a preparation method of a compound shown as a formula 5, which comprises the following steps: in an organic solvent, in the presence of alkali and a condensing agent, carrying out a condensation reaction as shown in the specification on a compound shown in a formula 3 and a compound shown in a formula 4;
wherein,R1is tert-butyldimethylsilyl (TBS), dimethyltert-hexylsilyl (TDS) or allyloxycarbonyl (Alloc);
R2is naphthylmethyl (Nap), benzyl (Bn) or p-methoxybenzyl.
In the preparation method of the compound shown as the formula 5, R1Preferably tert-butyldimethylsilyl; r2Naphthyl methyl is preferred.
In the preparation method of the compound shown in formula 5, the organic solvent can be an organic solvent conventional in the art, and preferably a halogenated hydrocarbon solvent (e.g. dichloromethane).
In the preparation method of the compound shown in the formula 5, the base can be a base conventional in the art, and is preferably an organic base, such as 4-Dimethylaminopyridine (DMAP).
In the method for preparing the compound represented by formula 5, the condensing agent may be a condensing agent conventional in the art, and preferably one or more of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), Dicyclohexylcarbodiimide (DCC) and N, N' -Diisopropylcarbodiimide (DIC), such as 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
In the preparation method of the compound shown in the formula 5, the molar ratio of the base to the compound shown in the formula 3 can be a molar ratio which is conventional in the field, and is preferably 1:3-1:10 (such as 1:5.1), and more preferably 1:5-1: 7.
In the preparation method of the compound shown in the formula 5, the molar ratio of the condensing agent to the compound shown in the formula 3 can be a molar ratio which is conventional in the field, preferably 1:1-5:1 (such as 2:1), and more preferably 1:1-3: 1.
In the preparation method of the compound shown in the formula 5, the molar ratio of the compound shown in the formula 4 to the compound shown in the formula 3 can be a molar ratio which is conventional in the art, and is preferably 1:1-5:1 (such as 1.5:1), and more preferably 1:1-3: 1.
In the preparation method of the compound shown in the formula 5, the molar concentration of the compound shown in the formula 3 in the organic solvent can be a molar concentration conventional in the art, and is preferably 0.1-0.5mol/L (e.g. 0.14mol/L), and more preferably 0.1-0.3 mol/L.
In the preparation method of the compound shown in the formula 5, the condensation reaction temperature can be a temperature conventional in the reaction in the field, and is preferably 10-40 ℃.
In the preparation method of the compound represented by the formula 5, the progress of the condensation reaction can be monitored by means conventional in the art (such as TLC, HPLC or LCMS), and the time of the condensation reaction is preferably 2-6h (such as 4 h).
The post-treatment of the condensation reaction may be a post-treatment conventional in the art, further comprising the steps of: extracting, collecting organic layer, concentrating, separating and purifying. The solvent for the extraction is preferably a halogenated hydrocarbon solvent (e.g., methylene chloride) and a sodium bicarbonate solution (e.g., a saturated sodium bicarbonate solution) in that order. Before the concentration, the organic layer is preferably dried, and the dried reagent is preferably anhydrous sodium sulfate. The separation and purification is preferably column chromatography, the developing solvent is preferably a mixed solvent of an ether solvent (such as petroleum ether) and an ester solvent (such as ethyl acetate), and the volume ratio of the ether solvent to the ester solvent is preferably 10:1-30:1 (such as 20: 1).
The preparation method of the compound shown in the formula 5 further comprises the following steps: in an organic solvent, in the presence of organic acid, carrying out the reaction shown as the following on a compound shown as a formula 2 and 2- (dimethoxymethyl) -naphthalene to obtain a compound shown as a formula 3;
wherein R is1As defined in any of the previous schemes.
The organic solvent may be an organic solvent conventional in the art, preferably a nitrile solvent (e.g., acetonitrile).
The organic acid may be an organic acid conventional in the art, preferably camphorsulfonic acid or p-toluenesulfonic acid, such as camphorsulfonic acid.
The molar ratio of said 2- (dimethoxymethyl) -naphthalene to said compound of formula 2 may be a molar ratio as conventional in the art, preferably 1:1 to 5:1 (e.g. 1.5:1, 2:1), more preferably 1:1 to 3: 1.
The molar ratio of the organic acid to the compound of formula 2 may be any molar ratio conventional in the art, preferably 0.1:1 to 0.5:1 (e.g., 0.1:1, 0.2:1), more preferably 0.1:1 to 0.3: 1.
The molar concentration of the compound represented by formula 2 in the organic solvent may be a molar concentration conventional in the art, and is preferably 0.1 to 0.5mol/L (e.g., 0.34mol/L), and more preferably 0.3 to 0.5 mol/L.
The temperature of the reaction may be a temperature conventional in the art, preferably 10-40 ℃.
The progress of the reaction can be monitored by means conventional in the art (e.g. TLC, HPLC or LCMS), preferably for a period of 2-6h (e.g. 4 h).
The post-treatment of the reaction may be a post-treatment conventional in the art, further comprising the steps of: adjusting pH to neutral with alkali, extracting, concentrating, separating and purifying. The base is preferably an organic amine (e.g. triethylamine). The solvent for the extraction is preferably a halogenated hydrocarbon solvent (e.g., methylene chloride) and a sodium bicarbonate solution (e.g., a saturated sodium bicarbonate solution) in that order. Before the concentration, the organic layer is preferably dried and filtered, and the dried reagent is preferably anhydrous sodium sulfate. The separation and purification is preferably carried out by silica gel sand core funnel separation, the developing solvent is preferably a mixed solvent of an ether solvent (such as petroleum ether) and an ester solvent (such as ethyl acetate), and the volume ratio of the ether solvent to the ester solvent is preferably 1:1-10:1 (such as 5: 1).
The invention provides a preparation method of a compound shown as a formula 6, which comprises the following steps:
(1) preparing a compound shown in a formula 5 according to the preparation method of any scheme;
(2) in an organic solvent, carrying out the following reaction on a compound shown as a formula 5;
wherein R is1And R2As defined in any of the previous schemes.
In step (2), the reaction conditions and operations are the same as those conventional in this type of reaction in the art.
The invention provides a preparation method of a compound shown as a formula 7, which comprises the following steps:
(1) preparing a compound shown in a formula 6 according to the preparation method of any scheme;
(2) in an organic solvent, in the presence of alkali and a condensing agent, carrying out a condensation reaction as shown in the specification on a compound shown in a formula 6 and a compound shown in a formula 4;
wherein R is1And R2As defined in any of the previous schemes.
In step (2), the organic solvent may be an organic solvent conventional in the art, preferably a halogenated hydrocarbon solvent (e.g., dichloromethane).
In step (2), the base may be a base conventional in the art, preferably an organic base (e.g., 4-dimethylaminopyridine).
In step (2), the condensing agent may be a condensing agent conventional in the art, preferably one or more of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), Dicyclohexylcarbodiimide (DCC) and N, N' -Diisopropylcarbodiimide (DIC), for example 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
In step (2), the molar ratio of the base to the compound represented by formula 6 may be a molar ratio conventional in the art, preferably 1:3 to 1:30 (e.g., 1:26.5), more preferably 1:25 to 1: 28.
In step (2), the molar ratio of the condensing agent to the compound represented by formula 6 may be a molar ratio conventional in the art, preferably 1:1 to 5:1 (e.g., 2.7:1), more preferably 1:1 to 3: 1.
In step (2), the molar ratio of the compound represented by formula 4 to the compound represented by formula 6 may be a molar ratio conventionally used in the art, and is preferably 1:1 to 5:1 (e.g., 1.6:1), more preferably 1:1 to 3: 1.
In the step (2), the molar concentration of the compound represented by the formula 6 in the organic solvent may be a molar concentration conventional in the art, and is preferably 0.1 to 0.5mol/L (e.g., 0.11mol/L), and more preferably 0.1 to 0.3 mol/L.
In step (2), the condensation reaction may be carried out at a temperature conventional in the art for such reactions, preferably 10 to 40 ℃.
In step (2), the progress of the condensation reaction can be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), and the condensation reaction time is preferably 8-16 h.
In step (2), the post-treatment of the condensation reaction may be a post-treatment conventional in the art, and further comprises the following steps: extracting, collecting organic layer, concentrating, separating and purifying. The solvent for the extraction is preferably a halogenated hydrocarbon solvent (e.g., methylene chloride) and a sodium bicarbonate solution (e.g., a saturated sodium bicarbonate solution) in that order. The separation and purification is preferably column chromatography, the developing solvent is preferably a mixed solvent of an ether solvent (such as petroleum ether) and an ester solvent (such as ethyl acetate), and the volume ratio of the ether solvent to the ester solvent is preferably 5:1-15:1 (such as 10: 1).
The invention provides a preparation method of a compound shown as a formula 8, which comprises the following steps:
(1) preparing a compound shown in a formula 7 according to the preparation method of any scheme;
(2) in an organic solvent, carrying out the following reaction on a compound shown as a formula 7;
wherein R is1And R2As defined in any of the previous schemes.
In the step (2), the reaction conditions and operation are the same as those of the conventional reaction.
The invention provides a preparation method of a compound shown as a formula 9, which comprises the following steps:
(1) preparing a compound shown in a formula 8 according to the preparation method of any scheme;
(2) mixing the mixture A with a lithium reagent; the mixture A comprises an organic solvent, a compound shown as a formula 8 and a phosphorus-containing reagent;
(3) carrying out the following reaction on the compound shown in the formula 8 and the phosphorus-containing reagent;
wherein R is2As defined in any of the previous schemes.
In step (2), the organic solvent may be an organic solvent conventional in the art, preferably an etheric solvent (e.g., tetrahydrofuran).
In step (2), the lithium reagent is preferably lithium bis (trimethylsilyl) amide (LHMDS).
In the step (2), the phosphorus-containing reagent is preferably tetrabenzyl pyrophosphate.
In step (2), the molar ratio of the phosphorus-containing reagent to the compound represented by formula 8 may be a molar ratio conventional in the art, preferably 3:1 to 7:1 (e.g., 5.1:1), more preferably 5:1 to 7: 1.
In step (2), the volume molar ratio of the lithium reagent to the compound represented by formula 8 may be a molar ratio conventional in the art, preferably 2:1 to 8:1 (e.g., 4.5:1), and more preferably 4:1 to 6: 1.
In the step (2), the molar concentration of the compound represented by the formula 8 in the organic solvent may be a molar concentration conventional in the art, and is preferably 0.01 to 0.05mol/L (e.g., 0.02mol/L), and more preferably 0.01 to 0.03 mol/L.
In certain preferred embodiments of the present invention, in step (2), the lithium reagent is preferably added dropwise. The temperature of the mixture A is preferably-90 ℃ to-70 ℃ (for example-78 ℃) before the mixture A is mixed with the lithium reagent.
In step (3), the reaction is preferably carried out under a protective gas atmosphere, and the protective gas may be a protective gas conventional in the art, preferably nitrogen and/or argon.
In the step (3), the reaction temperature may be a reaction temperature conventional in the art, and is preferably-90 ℃ to-70 ℃ (e.g., -78 ℃).
In step (3), the progress of the reaction can be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), and the reaction time is preferably 0.5 to 4h (e.g., 1 h).
In step (3), the post-treatment of the reaction may be a post-treatment conventional in the art, and further comprises the following steps: quenching reaction, adjusting pH to neutral with alkali, extracting, concentrating, separating and purifying. The solvent for quenching is preferably an alcoholic solvent (e.g., methanol). The base is preferably an organic amine (e.g. triethylamine). The solvent for the extraction is preferably a halogenated hydrocarbon solvent (e.g., methylene chloride) and a sodium bicarbonate solution (e.g., a saturated sodium bicarbonate solution). Before the concentration, the organic layer is preferably dried and filtered, and the dried reagent is preferably anhydrous sodium sulfate. The separation and purification are preferably carried out by a C18 column.
The invention provides a preparation method of a compound shown as a formula 9, which comprises the following steps:
(1) mixing the mixture A with a lithium reagent; the mixture A comprises an organic solvent, a compound shown as a formula 8 and a phosphorus-containing reagent;
(2) carrying out the following reaction on the compound shown in the formula 8 and the phosphorus-containing reagent;
wherein R is2As defined in any of the previous schemes.
The organic solvent may be an organic solvent conventional in the art, and preferably an etheric solvent (e.g., tetrahydrofuran).
The lithium reagent is preferably lithium bis (trimethylsilyl) amide (LHMDS).
The phosphorus-containing reagent is preferably tetrabenzyl pyrophosphate.
The molar ratio of the phosphorus-containing reagent to the compound of formula 8 may be any molar ratio conventional in the art, preferably from 3:1 to 7:1 (e.g., 5.1:1), more preferably from 5:1 to 7: 1.
The volume molar ratio of the lithium reagent to the compound of formula 8 may be any molar ratio conventional in the art, preferably from 2:1 to 8:1 (e.g., 4.5:1), more preferably from 4:1 to 6: 1.
The molar concentration of the compound represented by the formula 8 in the organic solvent may be a molar concentration conventional in the art, and is preferably 0.01 to 0.05mol/L (e.g., 0.02mol/L), and more preferably 0.01 to 0.03 mol/L.
In certain preferred embodiments of the invention, the lithium reagent is preferably added dropwise. The temperature of the mixture A is preferably-90 ℃ to-70 ℃ (for example-78 ℃) before the mixture A is mixed with the lithium reagent.
The reaction is preferably carried out under an atmosphere of protective gas, which may be a protective gas customary in the art, preferably nitrogen and/or argon.
The reaction temperature may be a reaction temperature conventional in the art, preferably-90 ℃ to-70 ℃ (e.g., -78 ℃).
The progress of the reaction can be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), preferably for a period of 0.5 to 4h (e.g., 1 h).
The post-treatment of the reaction may be a post-treatment conventional in the art, further comprising the steps of: quenching reaction, adjusting pH to neutral with alkali, extracting, concentrating, separating and purifying. The solvent for quenching is preferably an alcoholic solvent (e.g., methanol). The base is preferably an organic amine (e.g. triethylamine). The solvent for the extraction is preferably a halogenated hydrocarbon solvent (e.g., methylene chloride) and a sodium bicarbonate solution (e.g., a saturated sodium bicarbonate solution). Before the concentration, the organic layer is preferably dried and filtered, and the dried reagent is preferably anhydrous sodium sulfate. The separation and purification are preferably carried out by a C18 column.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, carrying out the following reaction on the compound shown as the formula 7 to obtain a compound shown as a formula 8;
wherein R is1And R2As defined in any of the previous schemes.
The reaction conditions and operation are the same as those described above.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, in the presence of alkali and a condensing agent, carrying out a condensation reaction shown in the following formula on a compound shown in a formula 6 and a compound shown in a formula 4 to obtain the compound shown in the formula 7;
wherein R is1And R2As defined in any of the previous schemes.
The conditions and operation of the condensation reaction are the same as those of the reaction described above.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, carrying out the following reaction on the compound shown as the formula 5 to obtain the compound shown as the formula 6;
wherein R is1And R2As defined in any of the previous schemes.
The reaction conditions and operation are the same as those described above.
The invention provides a preparation method of a compound shown as a formula 10, which comprises the following steps:
in an organic solvent, in the presence of hydrogen and a palladium catalyst, carrying out a reduction reaction on a compound shown as a formula 9 as shown in the specification;
wherein R is2As defined in any of the previous schemes.
The solvent may be a solvent conventional in the art, and is preferably a mixed solvent of an etheric solvent (e.g., tetrahydrofuran) and water. The volume ratio of the ether solvent to water is preferably (70-90): (1-20) (for example, 85: 15).
The palladium catalyst is preferably palladium carbon (for example, palladium carbon with a mass fraction of 10%).
The mass molar ratio of the palladium catalyst to the compound represented by the formula 9 is preferably 1 to 5g/mmol (e.g., 2g/mmol), more preferably 1 to 3 g/mmol.
The pressure of the hydrogen is preferably 10 to 20kg/cm2(e.g., 15 kg/cm)2) More preferably 15 to 20kg/cm2。
The molar concentration of the compound represented by the formula 9 in the organic solvent may be a molar concentration conventional in the art, and is preferably 1 to 5mmol/L (e.g., 3.4mmol/L), and more preferably 3 to 5 mmol/L.
The temperature of the reduction reaction may be a reaction temperature conventional in the art, preferably 20 to 60 ℃ (e.g., 38 ℃), more preferably 30 to 50 ℃.
The progress of the reduction reaction can be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), and the reaction time is preferably 8-16 h.
The post-treatment of the reduction reaction may be a post-treatment conventional in the art, further comprising the steps of: quenching reaction, filtering, concentrating filtrate, separating and purifying to obtain the product. The solvent for quenching is preferably an organic amine (e.g., triethylamine). The separation and purification are preferably carried out by a C18 column.
The invention provides a preparation method of a compound shown as a formula 10, which comprises the following steps:
(1) preparing a compound shown as a formula 9 according to any one of the preparation methods;
(2) in an organic solvent, in the presence of hydrogen and a palladium catalyst, carrying out a reduction reaction on a compound shown as a formula 9 as shown in the specification;
wherein R is2As defined in any of the previous schemes.
In the step (2), the conditions and operation of the reduction reaction are the same as those of the reaction described above.
The present invention provides a compound as shown below,
wherein R is1And R2As defined in any of the previous schemes.
The present invention provides a compound as shown below,
in the present invention, room temperature means 10 to 40 ℃ unless otherwise specified; "h" means hours; "overnight reaction" means reaction for 8-16 hours.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the synthesis route of Lipid X disclosed by the invention is novel, and the yield is higher.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1.
After the consumption of the raw materials detected by TLC, the reaction solution was neutralized with cationic resin, filtered and concentrated, the product was extracted with dichloromethane and saturated sodium bicarbonate solution, the organic layer was collected and concentrated to obtain 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino- β -D-glucose (2-1,8.23 g).
In a reaction flask, 2-1 and 2- (dimethoxymethyl) -naphthalene (5.1g, 25mmol, 1.5eq) were dissolved in 50mL acetonitrile, camphorsulfonic acid (0.39g, 1.69mmol, 0.1eq) was added, the reaction was stirred at room temperature for 4h, triethylamine was added to neutrality, the reaction solution was extracted with dichloromethane and saturated sodium bicarbonate solution, and the solution was separated. The organic phase was dried and dried to give a yellow solid. The crude product was passed through a silica gel frit funnel (PE: EA ═ 5:1) to afford product 3-1 (pale yellow solid, 6.97g) in 68.3% yield over two steps.
Compound 3-1:1H NMR(400MHz,CDCl3)δ7.96–7.50(m,7H),5.72(s,1H),5.17(d,J＝6.3Hz,1H),4.88(d,J＝7.7Hz,1H),4.73(q,J＝12.0Hz,2H),4.36(dd,J＝10.5,5.0Hz,1H),4.13–4.01(m,1H),3.86(t,J＝10.3Hz,1H),3.70–3.58(m,1H),3.52(td,J＝9.7,5.0Hz,1H),3.47–3.35(m,1H),2.96(s,1H),0.94(d,J＝8.2Hz,9H),0.20–0.08(m,6H).
13C NMR(101MHz,CDCl3)δ154.54,134.52,133.78,132.87,128.41,128.29,127.75,126.69,126.41,126.07,123.93,101.97,96.33,95.30,81.52,74.85,70.71,68.68,66.20,60.73,26.94,25.59,17.90,-4.14,-5.26.
example 2.
After a reaction flask added with 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-3, 4, 6-triacetyl-beta-D-glucose (10g, 16.8mmol) is slowly added with a guanidinidine hydrochloride buffer solution (100mL, pH 8), stirred at room temperature for 3.5h, TLC detects that the raw material is consumed, the reaction solution is washed with methanol three times and neutralized with cationic resin, filtered, the filtrate is concentrated, the product is extracted with dichloromethane and saturated sodium bicarbonate solution, the collected organic layer is concentrated to obtain 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-beta-D-glucose (2-1,8.5 g).
In a reaction flask, 2-1 and 2- (dimethoxymethyl) -naphthalene (5.1g, 25mmol, 1.5eq) were dissolved in 50mL acetonitrile, camphorsulfonic acid (0.78g, 3.37mmol, 0.2eq) was added, the reaction was stirred at room temperature for 4h, triethylamine was added to neutrality, the reaction solution was extracted with dichloromethane and saturated sodium bicarbonate solution, and the solution was separated. The organic phase was dried and dried to give a yellow solid. The crude product was passed through a silica gel frit funnel (PE: EA ═ 5:1) to afford product 3-1 (pale yellow solid, 5.05g) in 49.5% yield.
Of Compound 3-11H NMR and13c NMR was the same as in example 1.
Example 3.
After a reaction flask added with 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-3, 4, 6-triacetyl-beta-D-glucose (10g, 16.8mmol) is slowly added with a guanidinidine hydrochloride buffer solution (100mL, pH 8), stirred at room temperature for 3.5h, TLC detects that the raw material is consumed, the reaction solution is washed with methanol three times and neutralized with cationic resin, filtered, the filtrate is concentrated, the product is extracted with dichloromethane and saturated sodium bicarbonate solution, the collected organic layer is concentrated to obtain 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-beta-D-glucose (2-1,8.9 g).
In a reaction flask, 2-1 and 2- (dimethoxymethyl) -naphthalene (6.8g, 33.7mmol, 2eq) were dissolved in 50mL acetonitrile, camphorsulfonic acid (0.39g, 1.69mmol, 0.1eq) was added, the reaction was stirred at room temperature for 4h, triethylamine was added to neutrality, the reaction solution was extracted with dichloromethane and saturated sodium bicarbonate solution, and the solution was separated. The organic phase was dried and dried to give a yellow solid. The crude product was passed through a silica gel frit funnel (PE: EA ═ 5:1) to afford product 3-1 (pale yellow solid, 7.1g) in 69.6% yield.
Of Compound 3-11H NMR and13c NMR was the same as in example 1.
Example 4.
After a reaction flask added with 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-3, 4, 6-triacetyl-beta-D-glucose (10g, 16.8mmol) is slowly added with a guanidinidine hydrochloride buffer solution (100mL, pH 9), stirred at room temperature for 3.5h, TLC detects that the raw material is consumed, the reaction solution is washed with methanol three times and neutralized with cationic resin, filtered, the filtrate is concentrated, the product is extracted with dichloromethane and saturated sodium bicarbonate solution, the collected organic layer is concentrated to obtain 2-deoxy-1-oxo- (1, 1-dimethylethyl) dimethylsilyl-2- [ (2,2, 2-trichloroethoxy) carbonyl ] amino-beta-D-glucose (2-1,10g) in that respect
In a reaction flask, 2 and 2- (dimethoxymethyl) -naphthalene (5.1g, 25mmol, 1.5eq) were dissolved in 50mL acetonitrile, camphorsulfonic acid (0.39g, 1.69mmol, 0.1eq) was added, the reaction was stirred at room temperature for 4h, triethylamine was added to neutral, the reaction solution was extracted with dichloromethane and saturated sodium bicarbonate solution, and the layers were separated. The organic phase was dried and dried to give a yellow solid. The crude product was passed through a silica gel frit funnel (PE: EA:. gtoreq.5: 1) to afford product 3-1 (pale yellow solid, 4.1g) in 40.2% yield.
Of Compound 3-11H NMR and13c NMR was the same as in example 1.
Example 5.
3-1(0.5g, 0.82mmol) and (R) -3-naphthoxytetradecanoic acid (0.48g, 1.23mmol) were added to 6mL of dichloromethane, followed by EDC. HCl (0.2g, 1.65mmol) and DMAP (32mg, 0.16mmol) under ice-bath conditions. The mixture was allowed to warm to room temperature and stirred for an additional 4 h. The mixture was extracted with 50mL of dichloromethane and 50mL of saturated sodium bicarbonate solution, and the layers were separated. Drying the organic layer (Na)2SO4) The filtrate was filtered and concentrated. Crude silica gel column chromatography (20: 1 petroleum ether/ethyl acetate) gave 5-1 (an oily liquid, 0.76g,94.77％)。
compound 5-1:1H NMR(400MHz,CDCl3)δ7.81(1H,s),7.76–7.61(7H,m),7.48–7.35(5H,m),7.30(1H,d,J＝8.4),5.50(1H,s),5.39(1H,t,J＝9.9),5.24(1H,d,J＝9.1),4.84(1H,d,J＝7.8),4.67–4.62(3H,m),4.52(1H,d,J＝11.8),4.31(1H,dd,J＝10.4,4.7),3.85–3.81(1H,m),3.78(1H,d,J＝10.3),3.71(1H,t,J＝9.5),3.67–3.60(1H,m),3.53(1H,td,J＝9.5,5.1),2.74(1H,dd,J＝14.9,6.0),2.55(1H,dd,J＝14.8,5.6),1.54(2H,m),1.27(18H,s),0.91(12H,s),0.13(6H,d,J＝12.0).
13C NMR(101MHz,CDCl3)δ171.82,154.36,136.11,134.41,133.85,133.41,133.13,132.99,128.53,128.28,128.23,128.11,127.88,127.85,126.60,126.51,126.31,126.20,126.04,125.96,125.91,123.85,101.88,97.14,79.18,75.73,74.88,71.39,71.28,68.91,66.76,60.64,59.29,39.77,34.71,32.15,29.87,29.86,29.80,29.77,29.58,25.74,25.45,22.92,21.28,18.08,14.43,14.37,-3.98,-5.08.
example 6.
The first step is as follows: zinc powder (3g) was added portionwise to 5-1(1.7g,1.75mmol) dissolved in 40mL of dichloromethane, followed by acetic acid (4 mL). After completion of the reaction, the reaction mixture was filtered, concentrated to dryness, extracted with dichloromethane and saturated brine, and the resulting extract was separated, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to give 1.69g of a crude product.
The second step is that: EDC. HCl (1.08g, 5.65mmol), (R) -3-naphthoxytetradecanoic acid (1.3g, 3.39mmol) was dissolved in 20mL of dichloromethane and stirred for about 10mins, then the crude product (1.69g,2.12mmol) obtained in the first step was added, DMAP (10mg,0.08mmol) was added and stirred overnight, after completion of the reaction, 20mL of dichloromethane and 20mL of saturated sodium bicarbonate were extracted, and the crude product was chromatographed on silica gel (petroleum ether/ethyl acetate 10:1) to obtain 7-1. Yield: 1.37g, yield: 67.49 percent.
Compound 7-1:1H NMR(400MHz,CDCl3)δ7.98–7.51(m,21H),6.47(d,J＝9.3Hz,1H),5.47(s,1H),5.28(t,J＝9.9Hz,1H),4.90–4.47(m,4H),4.35(d,J＝7.8Hz,1H),4.23(dd,J＝10.4,4.9Hz,1H),3.97(dd,J＝18.1,9.5Hz,1H),3.91–3.80(m,2H),3.74(dd,J＝13.0,7.5Hz,1H),3.70–3.61(m,1H),3.15(tt,J＝15.9,7.9Hz,1H),2.73(dd,J＝14.7,6.4Hz,1H),2.54–2.41(m,3H),1.69–1.48(m,4H),1.28(s,36H),0.94–0.88(m,15H),0.07–0.01(m,6H).
MS[M+H]+:1164.89.
example 7.
At room temperature, 7-1(1.2g, 1.03mmol) and 6mL tetrahydrofuran were mixed in a fluorination flask with stirring, and after cooling to-40 ℃ with liquid nitrogen, 18mL pyridine-diluted hydrofluoric acid/pyridinium salt (3.6mL, 65-70%) was added and allowed to slowly warm to room temperature overnight for reaction. After the reaction was complete, 30mL of saturated sodium bicarbonate solution was added and quenched. Then, 30mL of dichloromethane was added for extraction and liquid separation. Drying the organic layer (Na)2SO4) The filtrate was filtered and concentrated. The crude product was purified by C18 column chromatography (acetonitrile, methanol/dichloromethane to yield the product 8-1 as a white solid, 0.85g, 78.7%).
Compound 8-1:1H NMR(400MHz,CDCl3)δ7.90–7.31(m,21H),6.42(d,J＝9.3Hz,1H),5.49(s,2H),5.45(t,J＝10.2Hz,1H),5.09(d,J＝3.5Hz,1H),4.73–4.47(m,4H),4.39–4.32(m,1H),4.22(dd,J＝10.3,4.9Hz,1H),4.08(td,J＝9.9,4.8Hz,1H),3.91–3.79(m,2H),3.74–3.64(m,2H),2.74–2.67(m,1H),2.51–2.43(m,1H),2.32(dd,J＝7.9,3.4Hz,2H),1.62–1.58(m,1H),1.46(ddd,J＝13.0,10.3,5.3Hz,3H),1.22(s,36H),0.88(t,J＝6.5Hz,6H).
MS[M+H]+:1050.46.
example 8.
8-1(0.15g,0.14mmol) and tetrabenzyl pyrophosphate (0.38g,0.71mmol) were dissolved in 7.5mL of ultra-dry tetrahydrofuran, N2Protecting, cooling to-78 deg.C, adding LHMDS (0.1g, 0.63mmol) dropwise, maintaining-78 deg.C, stirring for 1h, and reacting completely. Adding methanol for quenching, and adjusting triethylamine to be neutral. Saturated sodium bicarbonate was extracted with dichloromethane, anhydrous sodium sulfate was removed water, filtered, concentrated and the crude product was purified by C18 (acetonitrile, methanol/dichloromethane ═ 3:1) to give product 9-1 (white solid, 170.7mg, 91.2%).
Compound 9-1: MS [ M + Na ]]+:1332.61.
Example 9.
9-1(200mg,0.15mmol) was dissolved in 44.4mL tetrahydrofuran/water (85: 15)) Then 0.3g of 10% Pd/C was added at 15kg cm-2H2Under the condition, the reaction was carried out at 38 ℃ overnight. After the reaction was complete, quenched with one drop of triethylamine, filtered, the filtrate was collected and concentrated, and the crude product was purified by C18 (acetonitrile, methanol/dichloromethane ═ 3:1) to afford the final product 10-1 (white solid, 88mg, 80.7%).
Compound 10-1:1H NMR(400MHz,CDCl3)δ5.27(dd,J＝9.5,1H),6.45(d,J＝9.3Hz,1H)，5.25(dd,J＝3.5,7.5,1H),4.22(ddd,J＝10.5,2.5,1H),4.00(ddd,J＝5.6,1H),3.90(dd,J＝2.0,1.2,1H),3.87(m,1H),3.82(m,1H),3.75(dd,J＝12,1H),3.63(dd,J＝10,1H),2.75–2.67(m,1H),2.51–2.42(m,1H),2.32(dd,J＝7.9,3.4,2H),1.59(dd,J＝14.5,5.9,1H),1.47(ddd,J＝14.5,10.7,5.2,3H),1.22(s,36H),0.87(d,J＝7.1,6H).
MS[M-H]-:710.57.
comparative example 1
8-1(0.15g,0.14mmol) and LHMDS (0.14g, 0.84mmol) were dissolved in 10mL of ultra dry tetrahydrofuran, N2Protecting, cooling to-78 deg.C, adding tetrabenzyl pyrophosphate (0.5g,0.95mmol), maintaining at-78 deg.C, stirring for 1h, and reacting completely. Adding methanol for quenching, and adjusting triethylamine to be neutral. Saturated sodium bicarbonate was extracted with dichloromethane, anhydrous sodium sulfate was removed water, filtered, concentrated and the crude product was purified by C18 (acetonitrile, methanol/dichloromethane ═ 3:1) to give the final product 9-1 (white solid, 93mg, 37.2%).
Comparative example 2
8-1(0.15g,0.14mmol) and LHMDS (0.1g, 0.63mmol) were dissolved in 7.5mL of ultra dry tetrahydrofuran, N2Protecting, cooling to-78 deg.C, adding tetrabenzyl pyrophosphate (0.38g,0.71mmol), maintaining at-78 deg.C, stirring for 1h, and reacting completely. Adding methanol for quenching, and adjusting triethylamine to be neutral. Saturated sodium bicarbonate was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by C18 (acetonitrile, methanol/dichloromethane ═ 3:1) to give product 9-1 (white solid, 67mg, 35.8%).
Claims (10)
1. A preparation method of a compound shown as a formula 5 is characterized by comprising the following steps: in an organic solvent, in the presence of alkali and a condensing agent, carrying out a condensation reaction as shown in the specification on a compound shown in a formula 3 and a compound shown in a formula 4;
wherein R is1Is tert-butyldimethylsilyl, dimethyl-tert-hexylsilyl or allyloxycarbonyl;
R2is naphthylmethyl, benzyl or p-methoxybenzyl.
2. The process according to claim 1 for preparing a compound represented by the formula 5,
R1is tert-butyldimethylsilyl;
and/or, R2Is naphthyl methyl;
and/or the organic solvent is a halogenated hydrocarbon solvent, preferably dichloromethane;
and/or, the base is an organic base, preferably 4-dimethylaminopyridine;
and/or the condensing agent is one or more of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide and N, N' -diisopropylcarbodiimide, preferably 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
and/or the molar ratio of the alkali to the compound shown in the formula 3 is 1:3-1:10, preferably 1:5-1: 7;
and/or the molar ratio of the condensing agent to the compound shown in the formula 3 is 1:1-5:1, preferably 1:1-3: 1;
and/or the molar ratio of the compound shown as the formula 4 to the compound shown as the formula 3 is 1:1-5:1, preferably 1:1-3: 1;
and/or the molar concentration of the compound shown as the formula 3 in the organic solvent is 0.1-0.5mol/L, preferably 0.1-0.3 mol/L;
and/or the temperature of the condensation reaction is 10-40 ℃;
and/or the time of the condensation reaction is 2-6 h.
3. The method of claim 1 or 2, further comprising the steps of: in an organic solvent, in the presence of organic acid, carrying out the reaction shown as the following on a compound shown as a formula 2 and 2- (dimethoxymethyl) -naphthalene to obtain a compound shown as a formula 3;
4. the process according to claim 3 for preparing a compound represented by the formula 5,
the organic solvent is a nitrile solvent, preferably acetonitrile;
and/or the organic acid is camphorsulfonic acid or p-toluenesulfonic acid, preferably camphorsulfonic acid;
and/or the molar ratio of the 2- (dimethoxymethyl) -naphthalene to the compound shown as the formula 2 is 1:1-5:1, preferably 1:1-3: 1;
and/or the molar ratio of the organic acid to the compound shown as the formula 2 is 0.1:1-0.5:1, preferably 0.1:1-0.3: 1;
and/or the molar concentration of the compound shown as the formula 2 in the organic solvent is 0.1-0.5mol/L, preferably 0.3-0.5 mol/L;
and/or the reaction temperature is 10-40 ℃;
and/or the reaction time is 2-6 h.
5. A preparation method of a compound shown as a formula 6 is characterized by comprising the following steps:
(1) preparing a compound shown as a formula 5 according to the preparation method of any one of claims 1 to 4;
(2) in an organic solvent, carrying out the following reaction on a compound shown as a formula 5;
wherein R is1And R2Is as defined in claim 1 or 2.
6. A preparation method of a compound shown as a formula 7 is characterized by comprising the following steps:
(1) preparing a compound shown as a formula 6 according to the preparation method of claim 5;
(2) in an organic solvent, in the presence of alkali and a condensing agent, carrying out a condensation reaction as shown in the specification on a compound shown in a formula 6 and a compound shown in a formula 4;
wherein R is1And R2Is as defined in claim 1 or 2.
7. A preparation method of a compound shown as a formula 8 is characterized by comprising the following steps:
(1) preparing a compound shown as a formula 7 according to the preparation method of claim 6;
(2) in an organic solvent, carrying out the following reaction on a compound shown as a formula 7;
wherein R is1And R2Is as defined in claim 1 or 2.
8. A preparation method of a compound shown as a formula 9 is characterized by comprising the following steps:
(1) preparing a compound shown as a formula 8 according to the preparation method of claim 7;
(2) mixing the mixture A with a lithium reagent; the mixture A comprises an organic solvent, a compound shown as a formula 8 and a phosphorus-containing reagent;
(3) carrying out the following reaction on the compound shown in the formula 8 and the phosphorus-containing reagent;
wherein R is2Is as defined in claim 1 or 2.
9. The process according to claim 8 for preparing a compound represented by the formula 9,
in the step (2), the organic solvent is an ether solvent, preferably tetrahydrofuran;
and/or, in the step (2), the lithium reagent is lithium bis (trimethylsilyl) amide;
and/or, in the step (2), the phosphorus-containing reagent is preferably tetrabenzyl pyrophosphate;
and/or in the step (2), the molar ratio of the phosphorus-containing reagent to the compound shown in the formula 8 is 3:1-7:1, preferably 5:1-7: 1;
and/or, in the step (2), the volume mol ratio of the lithium reagent to the compound shown in the formula 8 is 2:1-8:1, preferably 4:1-6: 1;
and/or, in the step (2), the molar concentration of the compound shown in the formula 8 in the organic solvent is 0.01-0.05mol/L, preferably 0.01-0.03 mol/L;
and/or, in the step (2), the lithium reagent is added dropwise;
and/or in the step (2), before the mixture A is mixed with the lithium reagent, the temperature is-90 to-70 DEG C
And/or, in the step (3), the reaction is carried out under the atmosphere of protective gas, and the protective gas is preferably nitrogen and/or argon;
and/or, in the step (3), the reaction temperature is-90 ℃ to-70 ℃;
and/or, in the step (3), the reaction time is 0.5-4 h.
10. A compound represented by formula 3, formula 5, formula 6 or formula 7,
wherein R is1And R2As defined in claim 1 or 2;
the compound shown in the formula 3, the formula 5, the formula 6 or the formula 7 is preferably a compound shown in the formula 3-1, the formula 5-1, the formula 6-1 or the formula 7-1,
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Citations (4)
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|---|---|---|---|---|
| WO2002085929A1 (en) * | 2001-04-18 | 2002-10-31 | Eli Lilly And Company | Process for preparing lipid ii |
| US20100221269A1 (en) * | 2007-09-07 | 2010-09-02 | University Of Georgia Reseach Foundation, Inc | Synthetic lipid a derivative |
| CN102596220A (en) * | 2009-07-31 | 2012-07-18 | 韦恩州立大学 | Monophosphorylated lipid A derivatives |
| US20140328876A1 (en) * | 2011-11-18 | 2014-11-06 | Variation Biotechnologies Inc. | Synthetic derivatives of mpl and uses thereof |
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| WO2002085929A1 (en) * | 2001-04-18 | 2002-10-31 | Eli Lilly And Company | Process for preparing lipid ii |
| US20100221269A1 (en) * | 2007-09-07 | 2010-09-02 | University Of Georgia Reseach Foundation, Inc | Synthetic lipid a derivative |
| CN102596220A (en) * | 2009-07-31 | 2012-07-18 | 韦恩州立大学 | Monophosphorylated lipid A derivatives |
| US20140328876A1 (en) * | 2011-11-18 | 2014-11-06 | Variation Biotechnologies Inc. | Synthetic derivatives of mpl and uses thereof |
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