CN105175488A - Compound with anti-alzheimer's disease activity and preparation method thereof - Google Patents
Compound with anti-alzheimer's disease activity and preparation method thereof Download PDFInfo
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- CN105175488A CN105175488A CN201510564498.9A CN201510564498A CN105175488A CN 105175488 A CN105175488 A CN 105175488A CN 201510564498 A CN201510564498 A CN 201510564498A CN 105175488 A CN105175488 A CN 105175488A
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- 0 CCC(*(C)C[C@](C)C(CNC[C@@](Cc1ccccc1)C(N)=O)=O)=O Chemical compound CCC(*(C)C[C@](C)C(CNC[C@@](Cc1ccccc1)C(N)=O)=O)=O 0.000 description 1
Abstract
The invention discloses a compound with anti-alzheimer's disease activity which has a structure in formula (I), and the substituent R of the compound represents C1-C6 alkyl group, cycloalkyl group or aryl group. By structurally transforming the C-5 site of L-685-458, the method is adopted for the first time to successfully prepare the L-685-458, synthesize five types of new L-685-458 analogues, which have the advantages of high yield, easiness in separation, low cost, convenient production expansion and the like. Inferred according to the activity of the compound L-685-458, the five types of new L-685-458 analogues ought to have the anti-alzheimer's disease activity, and therefore have the prospect of being developed into anti-alzheimer's disease medicines.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the multiple compound with anti-senile dementia disease activity.Present invention also offers the preparation method of these compounds.
Background technology
Senile dementia, also known as alzheimer's disease (Alzheimerdisease, AD), is a kind of many interpretation of the cause, onset and process of an illness different substantiality disease, has the nervous system degenerative disease of characteristic neurological pathology and neurochemistry change.The cause of disease and the pathogenesis of senile dementia are still not clear so far, study mainly tubulin TAU Abnormal Phosphorylation at present and are formed caused by some transgenation on the abnormal hydrolysis of Amyloid Precursor (APP) in duplex mat-ups, film and false folding and karyomit(e).Dementia is defined as OMD disease by APA in " diagnostic and statistical manual ", and it is characterized in that intelligence (memory, judgement, abstract thinking) is lost widely, huge change occurs personality simultaneously.Senile dementia is modal dementia, and most of disease appears on the person of more than 50 years old, and initial morbidity is not easily discovered, and in slowly morbidity, causes this disease to all more serious when realizing.
According to the data presentation that WHO2012 announces April, there are nearly 3,560 ten thousand patients with Alzheimer disease in the whole world, and sickness rate is in rising trend, expects the year two thousand thirty, will be increased to 6,570 ten thousand people, and the year two thousand fifty will be increased to 1.154 hundred million people.Current China belongs to the serious country of aging, and the old man more than 60 years old is close to 1.3 hundred million, and the current patients of senile dementia of China accounts for greatly 5% of total population.And the age of the elderly often increases by 10 years old, sickness rate increases by 1 times.Expect 2025, the people had more than 1,000 ten thousand is suffered from alzheimer's disease by China.
Senile dementia brings heavy economical load to social development, and in the U.S., the direct or indirect economical load caused because of AD is every year up to 10,000,000,000 dollars, and China is no exception.Since senile dementia finds, namely developed country has dropped into the research of a large amount of new drug.Although there is many disputes in its pathogenesis and methods for the treatment of, but along with the progressively increase of the market requirement, some drug researches but obtain steady progress, more than 1000 compound that have found has anti-senile dementia disease activity, existing 13 medicines are ratified abroad for patient treatment at present, also have multiple compound to enter clinical study, but these medicines present many deficiencies in curative effect etc.Therefore, the new drug development of senile dementia still faces huge challenge.
China is very active at anti-senile dementia disease area research, and such as, existing 120 Yu Jia units carry out calf blood protein-removed extraction; 200 Yu Jia enterprises carry out ginkgo class (Ginkgo Leaf, the ginkgo Damo) research such as bulk drug, preparation, carry out research of huperzine Class A medicine etc. close to 50 companies, also have many Chinese medicine preparations to contend exploitation between many companies.Although many pharmacy corporations throw oneself into senile dementia research, because of factors, the new AD medicament research and development of real high efficiency low cost is still in bottleneck stage.Therefore, develop anti-senile dementia disease new drug and still face the most serious challenge.
The treatment AIDS-treating medicine that L-685-458 is researched and developed by Merck & Co., Inc. at first, what is interesting is, in the treatment AIDS-treating medicine of all similar listings, such as hydroxyethylene, lopinavir and ritonavir, wherein in hydroxyethylene structure, amino alcohol is (S, S) configuration, and has (S, R) the L-685-458 anti-HIV activity of configuration is very low, but antagonism senile dementia has extraordinary activity.Although Duo Jia unit carries out large quantity research, regrettably because its preparation difficulty waits factors, the structure of modification-structure activity study of its C-5 position is not yet carried out.
Summary of the invention
Structure of modification is carried out in the C-5 position that the present invention is directed to compound L-685-458, has prepared the L-685-458 analogue of a series of structure novel.These compounds can become the potential new activeconstituents with anti-senile dementia disease activity.The present invention gives a kind of novel method of synthesizing L-685-458 and analogue thereof.This synthesis route is easy, can amplify preparation, and combined coefficient is high and cost is synthesized in reduction.
The L-685-458 analogue of the present invention's synthesis has the chemical structure of formula I:
Wherein, substituent R represents C1-C6 alkyl, cycloalkyl group or aromatic base.
Further, substituent R is preferably C1-C6 straight chained alkyl, single-ring naphthene base, phenyl or naphthyl.
Alternatively base R's is preferred further, and substituent R can be ethyl, normal hexane base, cyclopropane base, phenyl or naphthyl.If substituent R is benzyl (Bn), be compound L-685-458 (the present invention is numbered 1a).Provide the particular chemical of 5 kinds of L-685-458 analogues below, concrete numbering is respectively 1b, 1c, 1d, 1e and 1f.
In order to the structure of full and accurate description formula I compound, the term in defining context of the present invention.
Term " alkyl " should refer to remove hydrogen atom and derivative univalent perssad from the either carbon atom of alkane, and the carbon atom of " alkyl " forms the skeleton of straight or branched, and therefore, " alkyl " can be divided into " straight chained alkyl " and " branched-chain alkyl ".This term comprises primary, secondary, tertiary alkyl subclass, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl.Especially, term " alkane " refers to the saturated hydrocarbon compound only containing carbon, hydrogen.
Term " aromatic base " can be called " aryl " again, should comprise carbon aromatic ring radical, and carbonatoms is C
6-C
10aromatic ring group, such as phenyl (C
6), naphthyl (C
10) and C
8aromatic ring group.
Term " naphthenic hydrocarbon " should refer to containing one or more ring filling hydrocarbon compound in molecular structure, or the stable hydrocarbon containing alicyclic structure, and have monocycle alicyclic ring and condensed ring alicyclic ring, simple naphthenic hydrocarbon has cyclopropane, tetramethylene, pentamethylene, hexanaphthene etc.Term " cycloalkyl group " removes hydrogen atom and derivative univalent perssad, such as cyclopropane base from naphthenic hydrocarbon either carbon atom.
Compound 1b, substituent R is phenyl.Compound 1c, substituent R is cyclopropane base.Compound 1d, substituent R is ethyl.Compound 1e, substituent R is naphthyl.Compound 1f, substituent R is normal hexane base.
In order to synthesize the L-685-458 and analogue thereof with formula I structure, The present invention gives preferred design and synthesis route.
Said synthesis route comprises the steps:
Step 1: compound 1 reacts 4-12 hour, extraction into ethyl acetate in a kind of ether/aqueous systems of alkali, after concentrated, be dissolved in tetrahydrofuran (THF), add pivaloyl chloride, oxazolidone and Lithium chloride (anhydrous) reaction 5-20 hour, purified compound 2.The said alkali of this step 1 refers to any one in sodium hydroxide, potassium hydroxide, lithium hydroxide, is particularly preferably lithium hydroxide.The said ether of this step 1 refers to any one in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), dihydropyrane, ether, is particularly preferably tetrahydrofuran (THF).
Compound 1 is the initial raw material of synthesis L-685-458.Compound 1 according to the synthetic route of bibliographical information from D-Glu prepare in a large number (compound 1 prepare reference literature: Winkler, J.W.; Uddin, J.; Serhan, C.N.; Petasis, N.A.; Org.Lett., 2013,15,1424.).
Step 2: compound 2 reacts 5-20 hour in the ether of a kind of alkali and a kind of benzyl halohydrocarbon, purified compound 3.The said alkali of this step 2 refers to any one in sodium hydride, LHMDS, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium tert.-butoxide, butyllithium, is particularly preferably sodium hexamethyldisilazide.The said phenyl halohydrocarbon of this step 2 refers to any one in Benzyl Chloride, cylite, iodate benzyl, is particularly preferably cylite.The said ether of this step 2 refers to any one in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), dihydropyrane, ether, is particularly preferably tetrahydrofuran (THF).
Step 3: compound 3 reacts 4-12 hour in the ether/aqueous systems of the first alkali, after acidifying, extraction into ethyl acetate, after concentrated, be dissolved in DMF, add the second alkali and iodomethane reaction 20-36 hour, purified compound 4.This step 3 the first alkali said refers to any one in sodium hydroxide, potassium hydroxide, lithium hydroxide, is particularly preferably lithium hydroxide.The said ether of this step 3 refers to any one in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), dihydropyrane, ether, is particularly preferably tetrahydrofuran (THF).The said the second alkali of this step 3 refers to any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, is particularly preferably sodium bicarbonate.
Step 4: through concentrated after compound 4 reacts 2-20 hour in the methylene dichloride of a kind of acid and a kind of alcohol, obtain compound 5, do not need separation and purification.The said acid of this step 4 refers to tosic acid or camphorsulfonic acid.The said alcohol of this step 4 refers to any one in methyl alcohol, ethanol, the trimethyl carbinol, n-Octanol, is particularly preferably methyl alcohol and ethanol.
Step 5: after compound 5 and a kind of oxygenant react 0.5-10 hour in methylene dichloride, directly concentratedly obtains crude product, not purifiedly directly under a kind of dewatering agent exists, reacts 10-50 hour with a kind of sulfinyl amine, and purifying obtains compound 6.
The said a kind of oxygenant of this step 5 refers to PCC, DMP, DMSO/ (COCl)
2.PCC is the abbreviation of Pyridiniumchlorochromate, also referred to as Corey-PCC reagent, be pyridine and the complexing salt of CrO3 in hydrochloric acid soln, be dissolved in methylene dichloride, destruction is not occurred to unsaturated link(age)s such as C=C, C=O, C=N of existing in compound molecule.DMP is the abbreviation of Dess-MartinPeriodinane, namely wears this Martin's oxygenant, also referred to as Dess-Martin height iodine reagent, is a kind of conventional, gentle, that selectivity is good oxidising agent.
The said sulfinyl amine of this step 5 refers to alkyl sulfenyl amine or aryl sulfinyl amine, is particularly preferably t-butyl sulfonamide.The said a kind of water-retaining agent of this step 5 refers to any one in anhydrous magnesium sulfate, anhydrous sodium sulphate, molecular sieve or anhydrous cupric sulfate, is particularly preferably anhydrous cupric sulfate.
Water-retaining agent molecular sieve, also known as synthetic zeolite, is the many microporous crystals of a kind of silico-aluminate.The type of molecular sieve is mainly divided into A type, X-type, Y type etc. by its crystalline structure, has strong water-absorbent.
Step 6: compound 6 reacts 1-20 hour, cancellation, extraction into ethyl acetate under existing with a kind of metal reagent and a kind of Lewis acid in a kind of organic solvent, concentrated, crude product is dissolved in methylene dichloride, adds tert-Butyl dicarbonate (Boc
2o), DMAP (DMAP) and triethylamine reaction 24-48 hour, obtain compound 7 through si-enriched plastic column chromatography.
The said a kind of organic solvent of this step 6 refers to any one in ether, toluene, methylene dichloride, benzene, tetrahydrofuran (THF), is particularly preferably tetrahydrofuran (THF).The said a kind of organometallic reagent of this step 6 refers to any one in MAGNESIUM METAL reagent, metallic zinc reagent, synthesis, refers to the alkyl halide of C1-C10 and benzyl, the naphthyl of replacement, the benzylzinc halide azoviolet of replacement of replacement especially.The said a kind of Lewis acid of this step 6 refers to any one in zinc chloride, magnesium chloride, boron trifluoride diethyl etherate.
Step 7: compound 7 reacts 4-12 hour in the ether/aqueous systems of the first alkali, after acidifying, extraction into ethyl acetate, concentrated, obtain compound 8, do not need separation and purification.The said a kind of alkali of this step 7 refers to any one in sodium hydroxide, potassium hydroxide, lithium hydroxide, is particularly preferably lithium hydroxide.The said ether of this step 7 refers to any one in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), dihydropyrane, ether, is particularly preferably tetrahydrofuran (THF).
Step 8: compound 8 and Leu-Phe-NH
212-24 hour is reacted, cancellation, extraction into ethyl acetate in a kind of condensing agent and a kind of organic bases, concentrated, obtain compound 9, do not need separation and purification.
The said condensing agent of this step 8 refers to DCC, DIC, EDCI, HATU, HBTU, HCTU, HAPyU, HBPyU, TBTU, TSTU, TNTU, BOP, PyBOP, PyAOP, DPP-Cl, DECP, DPPA, MPTA, BOP-Cl, is particularly preferably HATU.HATU, chemical name is 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, is a kind of medicine intermediate, as a kind of reduction, is usually applied in carboxyl and synthesizes among the reaction of peptide bond with amino.
The said a kind of organic bases of this step 8 refers to triethylamine, diethylamine, pyridine, DMAP (DMAP), morpholine, N-methylmorpholine, DIPEA (DIPEA), is particularly preferably DIPEA.
Step 9: compound 9 is at a kind of fluorochemical reaction 10-20 hour, and cancellation, filters, obtain target compound.The said a kind of fluorochemical of this step 9 refers to any one in hydrogen fluoride, Neutral ammonium fluoride, Methanaminium, N,N,N-trimethyl-, fluoride, tetra-n-butyl Neutral ammonium fluoride, tetrabutyl ammonium fluoride trihydrate (TBAF), is particularly preferably tetrabutyl ammonium fluoride trihydrate (TBAF).
Said synthesis route is the novel process of synthetic L-685-458.Compared with former synthetic route, synthetic route provided by the invention is novel, productive rate is high and product is easy to be separated, and can be described as the optimal route of this compounds of preparation.Reagent used in step 1-9 is common agents, greatly reduces the cost of preparation L-685-458, can be applicable to extensive preparation, conveniently can realize the preparation of 10-100 gram of level in the lab.
Adopt said synthesis route, the present invention has also synthesized the brand-new L-685-458 analogue of 5 kinds of structures, is synthesized first by the present invention.These 5 kinds of compounds (1b, 1c, 1d, 1e and 1f) are identical with the agent structure of L-685-458, activity according to L-685-458 can be inferred, it is active that compound 1b, 1c, 1d, 1e and 1f should have anti-senile dementia disease, can be used as the new activeconstituents of anti-senile dementia disease drug exploitation.
Further describe the present invention in the examples below, and be not intended in any form limit the protection scope of the present invention as indicated in claim.
Embodiment
Embodiment 1
Synthesis (R)-3-((R)-4,5-bis-(tertiary butyl dimethyl Si base) amylalcohol)-4-oxazolyl phenyl alkane-2-ketone (compound 2)
By compound 1 (10.0g, 26.5mmol) be dissolved in 120mL tetrahydrofuran (THF) and 40mL water, add a hydronium(ion) Lithium Oxide 98min (3.4g, 79.6mmol), stirring at room temperature 12 hours, extraction into ethyl acetate, after concentrated, be dissolved in 100mL tetrahydrofuran (THF), be cooled to-78 DEG C, add triethylamine (7.3mL, 53mmol), pivaloyl chloride (3.8g, 31.8mmol), oxazolidone (4.7g, 26.5mmol) with Lithium chloride (anhydrous) (3.4g, 79.6mmol), nature temperature reaction 10 hours, after shrend is gone out, extraction into ethyl acetate, dry, concentrated, silica column purification obtains white solid 2 (9.6g, 69%).
1HNMR(400MHz,CDCl
3)δ7.38-7.22(m,5H),4.72-4.65(m,1H),4.25-4.15(m,2H),3.84-3.77(m,1H),3.61(dd,J＝10.0,5.2Hz,1H),3.48(dd,J＝10.0,6.4Hz,1H),3.35(dd,J＝13.2,3.2Hz,1H),3.14-2.97(m,2H),2.77(dd,J＝13.2,9.6Hz,1H),2.10-2.00(m,1H),1.82-1.72(m,1H),0.93(s,9H),0.92(s,9H),0.12(s,3H),0.11(s,3H),0.10-0.08(m,6H)ppm.
Synthesis (R)-4-benzyl-3-((2R, 4R)-2-benzyl-4,5-bis-(tertiary butyl dimethyl Si base) amylalcohol)-4-oxazolyl phenyl alkane-2-ketone (compound 3)
Compound 2 (9.0g, 17.2mmol) is dissolved in 70mL tetrahydrofuran (THF), is cooled to-78 DEG C, instillation NaHMDS (8.6mL, 17.2mmol, 2MinTHF), stir 30 minutes, add cylite (6.1mL, 51.6mmol), nature temperature reaction 12 hours, after saturated ammonium chloride cancellation, extraction into ethyl acetate, dry, concentrated, silica column purification obtains white solid 3 (6.2g, 58%).
1HNMR(400MHz,CDCl
3)δ7.34-7.19(m,8H),7.14-7.12(m,2H),4.66-4.60(m,1H),4.39-4.32(m,1H),4.15-4.06(m,2H),3.69-3.64(m,1H),3.53(dd,J＝10.0,5.2Hz,1H),3.41(dd,J＝10.0,6.0Hz,1H),3.10-3.03(m,2H),2.84(dd,J＝13.2,8.0Hz,1H),2.39(dd,J＝13.2,9.6Hz,1H),2.02-1.95(m,1H),1.89-1.83(m,1H),0.91(s,9H),0.89(s,9H),0.10(s,3H),0.07(s,3H),0.05(s,3H),0.04(s,3H)ppm.
Synthesis (2R, 4R)-2-benzyl-4,5-bis-(tertiary butyl dimethyl Si base) methyl valerate (compound 4)
Compound 3 (6.0g, 9.8mmol) is dissolved in 120mL tetrahydrofuran (THF) and 30mL water, is cooled to 0 DEG C and adds hydronium(ion) Lithium Oxide 98min (1.2g, 29.4mmol) and a 30%H
2o
2(7.0mL, 68.6mmol), natural temperature reaction 12 hours, extracted with diethyl ether, after concentrated, add sherwood oil, filter, be dissolved in 20mLN after filtrate evaporate to dryness, in dinethylformamide, add sodium bicarbonate (1.7mL, 19.6mmol) with methyl iodide (3.1mL, 49mmol), room temperature reaction 24 hours, after saturated ammonium chloride cancellation, extraction into ethyl acetate, dry, concentrated, silica column purification obtains colorless oil 4 (2.7g, 59%).
1HNMR(400MHz,CDCl
3)δ7.32-7.15(m,5H),3.74-3.66(m,1H),3.59(s,3H),3.55(dd,J＝10.0,5.2Hz,1H),3.43(dd,J＝10.0,5.6Hz,1H),3.00-2.76(m,3H),1.91-1.77(m,2H),0.92-0.88(m,18H),0.08(s,3H),0.07(s,3H),0.05(s,6H)ppm.
Synthesis (2R, 4R)-2-benzyl-4-(tertiary butyl dimethyl Si base)-5-hydroxyl methyl (compound 5)
By compound 4 (2.5g, 5.4mmol) be dissolved in 10mL methylene dichloride and 10mL anhydrous methanol, be cooled to-40 DEG C, camphorate sulfonic acid, stir and add triethylamine cancellation after 8 hours, concentrated silica gel leaks through filter, obtains colourless liquid 5 (1.0g, 54%) after ethyl acetate and sherwood oil column chromatography.
1HNMR(400MHz,CDCl
3)δ7.32-7.28(m,2H),7.24-7.21(m,1H),7.17-7.15(m,2H),3.78-3.73(m,1H),3.62(s,3H),3.55-3.50(m,1H),3.47-3.41(m,1H),2.99-2.92(m,1H),2.82-2.75(m,2H),2.02-1.93(m,2H),1.77-1.70(m,1H),0.90(s,9H),0.07(s,3H),0.06(s,3H)ppm.
Synthesis (2R, 4R)-2-benzyl-4-(tertiary butyl dimethyl Si base) methyl valerate imines (compound 6)
By compound 2 (900mg, 2.6mmol) be dissolved in 10mL methylene dichloride, DMP (2.2g is added under room temperature, 5.2mmol) stir after 0.5 hour and filter with silica gel funnel, tertiary butyl sulphonamide (315mg, 2.6mmol) and anhydrous cupric sulfate (830mg, 5.2mmol) room temperature reaction filtering and concentrating after 2 days is added after directly concentrated, and obtain light yellow liquid 6 (834mg, 72%) through silica column purification.
1HNMR(400MHz,CDCl
3)δ7.89(d,J＝4.4Hz,1H),7.29-7.13(m,6H),4.70-4.43(m,1H),3.62-3.59(m,3H),3.00-2.87(m,1H),2.8(dd,J＝18.0,6.0Hz,1H),2.14-2.07(m,1H),1.90-1.84(m,1H),1.20(s,9H),0.90(s,9H),0.06-0.04(m,6H)ppm.
Synthesis (2S, 3R, 5R)-2,5-dibenzyl-4-tertiary butyl dimethyl Si base-6-tertbutyloxycarbonyl Cyclohexamide (compound 7)
Compound 6 (726mg, 1.6mmol) is dissolved in 10mL tetrahydrofuran (THF), at-78 DEG C, adds the Benzylphosphonium Bromide magnesium of 4.8mL1M, then natural temperature reaction 8 hours, after saturated ammonium chloride cancellation, extraction into ethyl acetate, dry, concentrated, obtain crude product, be dissolved in methylene dichloride, add Boc
2o (698mg, 3.2mmol), DMAP (196mg, 1.6mmol) and triethylamine (1.1mL, 8.0mmol) react 24 hours, and concentrated, silica column purification obtains colorless oil 7 (579mg, 71%).
1HNMR(400MHz,CDCl
3)δ7.35-7.20(m,8H),7.11-7.09(m,8H),4.34-4.29(m,1H),3.75-3.73(m,1H),3.26-3.22(m,1H),3.18-3.13(m,1H),3.05(dd,J＝13.2,8.0Hz,1H),2.92(dd,J＝13.6,5.2Hz,1H),2.12(dd,J＝13.6,10.8Hz,1H),1.87-1.80(m1H),1.71-1.64(m,1H),1.54(s,9H),0.77(m,9H),-0.17(s,3H),-0.22(s,3H)ppm.
Synthesis L-685-458
tert-Butyl
(2S,3R,5R)-5-(((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-yl)carbamoyl)-3-hydroxy-1,6-diphenylhexan-2-ylcarbamate(1a)
Compound 7 (306mg, 0.6mmol) is dissolved in 3mL tetrahydrofuran (THF) and 1mL water, is cooled to 0 DEG C and adds hydronium(ion) Lithium Oxide 98min (51mg, 1.2mmol) and a 30%H
2o
2(0.1mL), stirring reaction 4 hours, extraction into ethyl acetate, concentrates and obtains colorless oil 8.
Compound 8 and Leu-Phe-NH
2(306mg, 0.6mmol), HATU (343mg, 0.9mmol) and DIPEA (543mg, 4.2mmol) in methylene dichloride, react 12-24 hour, dchloromethane, saturated sodium bicarbonate washs, drying, concentrates and obtains colorless oil 9.
Compound 9 is dissolved in 5mLTBAF (1MinTHF), and stirring at room temperature reacts 12 hours, acidifying, filters and obtains white solid L-685-4581a (360mg, 89%).Spectral data is consistent with data in literature.
1HNMR(400MHz,DMSO)δ7.96-7.88(m,1H),7.73-7.64(m,1H),7.36-7.30(m,1H),7.28-7.06(m,16H),6.52(d,J＝9.2Hz,1H),4.75(d,J＝6.0Hz,1H),4.41(ddd,J＝13.6,8.0,5.6Hz,1H),4.25-4.14(m,1H),3.52-3.37(m,2H),3.00(dd,J＝14.0,5.2Hz,1H),2.87-2.65(m,4H),2.55(dd,J＝13.6,6.8Hz,1H),2.43(dd,J＝13.6,10.8Hz,1H),1.70-1.61(m1H),1.59-1.46(m,2H),1.43-1.30(m,2H),1.28-1.08(m,9H),0.88-0.72(m,6H)ppm.
Embodiment 2
The preparation method of preparation method's reference L-685-4581a of compound 1b.
tert-Butyl
(1S,2R,4R)-4-(((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-yl)carbamoyl)-2-hydroxy-1,5-diphenylpentylcarbamate(1b)
1HNMR(400MHz,CD
3OD)δ7.32-7.13(m,15H),4.63-4.59(m,1H),4.58-4.47(m,2H),4.22(dd,J＝10.0,5.6Hz,1H),3.90-3.80(m,1H),3.14(dd,J＝14.0,6.0Hz,1H),2.90-2.76(m,3H),2.70-2.62(m,1H),1.72-1.56(m,2H),1.54-1.34(m,11H),1.33-1.25(m,1H),0.92-0.86(m,3H),0.86-0.78(m,3H)ppm.
Embodiment 3
The preparation method of preparation method's reference L-685-4581a of compound 1c.
tert-Butyl
(1S,2R,4R)-5-((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-4-benzyl-1-cyclopropyl-2-hydroxy-5-oxopentylcarbamate(1c)
1HNMR(400MHz,CD
3OD)δ7.10-6.96(m,10H),4.43-4.38(m,1H),4.34(dd,J＝8.4,6.0Hz,1H),4.00(dd,J＝8.6,5.6Hz,1H),3.50-3.40(m,1H),2.95(dd,J＝14.0,6.0Hz,1H),2.74-2.62(m,3H),2.58-2.47(m,2H),1.74-1.55(m,2H),1.37-1.07(m,13H),0.76-0.65(m,4H),0.64-0.57(m,3H),0.24-0.10(m,2H),0.05--0.04(m,1H),-0.05--0.14(m,1H)ppm.
Embodiment 4
The preparation method of preparation method's reference L-685-4581a of compound 1d.
tert-Butyl
(3S,4R,6R)-7-((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-6-benzyl-4-hydroxy-7-oxoheptan-3-ylcarbamate(1d)
1HNMR(400MHz,CD
3OD)δ7.30-7.15(m,10H),4.63-4.56(m,2H),4.55-4.50(m,1H),4.20-4.14(m,1H),3.54-3.45(m,1H),3.20-3.11(m,1H),2.90-2.80(m,2H),2.79-2.67(m,2H),1.80-1.65(m,2H),1.60-1.35(m,13.5H),1.33-1.22(m,1.5H),0.92-0.84(m,6H),0.84-0.79(m,3H)ppm.
Embodiment 5
The preparation method of preparation method's reference L-685-4581a of compound 1e.
tert-Butyl
(1S,2R,4R)-5-((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-4-benzyl-2-hydroxy-1-(naphthalen-2-yl)-5-oxopentylcarbamate(1e)
1HNMR(400MHz,CD
3OD)δ7.85-7.70(m,4H),7.50-7.38(m,3H),7.29-7.22(m,2H),7.21-7.07(m,8H),4.73-4.66(m,1H),4.53-4.47(m,1H),4.23-4.15(m,1H),3.98-3.88(m,1H),3.13-3.06(m,1H),2.88-2.76(m,3H),2.70-2.58(m,1H),1.74-1.58(m,2H),1.55-1.33(m,11H),1.29-1.19(m,1H),0.88-0.73(m,6H)ppm.
Embodiment 6
The preparation method of preparation method's reference L-685-4581a of compound 1f.
tert-Butyl
(2R,4R,5S)-1-((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-benzyl-4-hydroxy-1-oxoundecan-5-ylcarbamate(1f)
1HNMR(400MHz,CDCl
3)δ7.18-7.04(m,10H),4.45-4.39(m,1H),4.11-4.05(m,1H),3.40-3.34(m,1H),3.31-3.24(m,1H),3.09-3.01(m,1H),2.80-2.71(m,2H),2.66-2.55(m,2H),1.70-1.60(m,1H),1.59-1.51(m,1H),1.45-1.26(m,13H),1.25-1.06(m,10.5H),0.82-0.75(m,6.5H),0.73-0.69(m,3H)ppm.
Further describe invention has been above, but the present invention is not limited to above-mentioned embodiment, in the ken that one skilled in the relevant art possesses, can also make a variety of changes under the prerequisite not departing from present inventive concept in conjunction with the embodiments.
Claims (10)
1. there is a compound for anti-senile dementia disease activity, it is characterized in that, there is the chemical structure of formula I:
Wherein, substituent R represents C1-C6 alkyl, cycloalkyl group or aromatic base.
2. the compound with anti-senile dementia disease activity according to claim 1, is characterized in that, described substituent R represents ethyl, normal hexane base, cyclopropane base, phenyl or naphthyl.
3. the compound with anti-senile dementia disease activity according to claim 1, is characterized in that, described substituent R is preferably C1-C6 straight chained alkyl, single-ring naphthene base, phenyl or naphthyl.
4. the compound with anti-senile dementia disease activity according to claim 1 or 2 or 3, is characterized in that having following structure:
5. have a preparation method with the compound of anti-senile dementia disease activity of formula I structure, adopt the reaction scheme comprising step 1-9:
R represents C1-C6 alkyl, cycloalkyl group or aromatic base.
Step 1, compound 1 reacts 4-12 hour in a kind of ether/aqueous systems of alkali, through extraction, concentrated after, be dissolved in tetrahydrofuran (THF), add pivaloyl chloride, oxazolidone and Lithium chloride (anhydrous) reaction 5-20 hour, purified compound 2;
Step 2, compound 2 reacts 5-20 hour in the ether of a kind of alkali and a kind of benzyl halohydrocarbon, purified compound 3;
Step 3, compound 3 reacts 4-12 hour in the ether/aqueous systems of the first alkali, after acidifying, through extraction, concentrated after, be dissolved in DMF, add the second alkali and iodomethane reaction 20-36 hour, purified compound 4;
Step 4, after compound 4 reacts 2-20 hour in the dichloromethane system of a kind of acid and a kind of alcohol, through concentrated, obtains compound 5;
Step 5, after compound 5 and a kind of oxygenant react 0.5-10 hour in dichloromethane system, directly concentrate and obtain crude product, directly under a kind of dewatering agent exists, react 10-50 hour with a kind of sulfinyl amine, purifying obtains compound 6;
Step 6, compound 6 reacts 1-20 hour with a kind of metal reagent and a kind of Lewis acid in a kind of organic solvent, cancellation, extraction, concentrated, crude product is dissolved in methylene dichloride, adds tert-Butyl dicarbonate, DMAP and triethylamine reaction 24-48 hour, obtains compound 7 through si-enriched plastic column chromatography;
Step 7: compound 7 reacts 4-12 hour in the ether/aqueous systems of the first alkali, after acidifying, extraction, concentrated, obtain compound 8;
Step 8, compound 8 and Leu-Phe-NH
212-24 hour is reacted, cancellation, extraction in a kind of condensing agent and a kind of organic bases, concentrated, obtain compound 9;
Step 9, compound 9 reacts 10-20 hour in a kind of fluorochemical, cancellation, filters, obtains target compound 1a-f.
6. preparation method according to claim 5, is characterized in that, the alkali described in step 1 is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, and described ether is selected from Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), dihydropyrane or ether.
7. preparation method according to claim 5, it is characterized in that, alkali described in step 2 is selected from sodium hydride, LHMDS, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium tert.-butoxide or butyllithium, described phenyl halohydrocarbon is selected from Benzyl Chloride, cylite or iodate benzyl, described ether is selected from Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), dihydropyrane or ether.
8. preparation method according to claim 5, it is characterized in that, the first alkali described in step 3 is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, described ether is selected from 1,4-dioxane, tetrahydrofuran (THF), dihydropyrane or ether, the second alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus.
9. preparation method according to claim 5, is characterized in that, the acid described in step 4 is selected from tosic acid or camphorsulfonic acid, and described alcohol is selected from methyl alcohol.
10. preparation method according to claim 5, is characterized in that, the oxygenant described in step 5 is selected from PCC, DMP or DMSO/ (COCl)
2, described sulfinyl amine is selected from alkyl sulfenyl amine or aryl sulfinyl amine, and described water-retaining agent is selected from anhydrous magnesium sulfate, anhydrous sodium sulphate, molecular sieve or anhydrous cupric sulfate; Organic solvent described in step 6 is selected from ether, toluene, methylene dichloride, benzene or tetrahydrofuran (THF), described organometallic reagent is selected from MAGNESIUM METAL reagent, metallic zinc reagent or synthesis, and described Lewis acid is selected from zinc chloride, magnesium chloride or boron trifluoride diethyl etherate; Alkali described in step 7 is selected from lithium hydroxide, and described ether is selected from tetrahydrofuran (THF); Condensing agent described in step 8 is selected from HATU, and described organic bases is selected from DIPEA; Fluorochemical described in step 9 is selected from tetrabutyl ammonium fluoride trihydrate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954923A (en) * | 2016-10-14 | 2018-04-24 | 复旦大学 | A kind of preparation method of orixine, halofuginone hydrobromide key chiral piperidine intermediate |
| CN108299545A (en) * | 2017-01-12 | 2018-07-20 | 复旦大学 | A method of preparing Symplocin A and its epimer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101027297A (en) * | 2004-07-28 | 2007-08-29 | 先灵公司 | Macrocyclic beta-secretase inhibitors |
| EP2153832A2 (en) * | 2003-12-15 | 2010-02-17 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
-
2015
- 2015-09-07 CN CN201510564498.9A patent/CN105175488A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2153832A2 (en) * | 2003-12-15 | 2010-02-17 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| CN101027297A (en) * | 2004-07-28 | 2007-08-29 | 先灵公司 | Macrocyclic beta-secretase inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| ALAN NADIN,ET AL.: "A stereocontrolled synthesis of 2R-benzyl-5S-tert-butoxycarbonylamino-4R-(tert-butyldimethylsilanyloxy)-6-phenyl-hexanoic acid (Phe±Phe hydroxyethylene dipeptide isostere)", 《TETRAHEDRON》 * |
| CHANG-MEI SI, ET AL.: "Diastereoconvergent Synthesis of trans-5-Hydroxy-6-Substituted-2-Piperidinones by Addition−Cyclization−Deprotection Process", 《ORG. LETT.》 * |
| MARK S. SHEARMAN,ET AL.: "L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity", 《BIOCHEMISTRY》 * |
| 刘润华: "海洋天然产物Haliclorensin的全合成研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954923A (en) * | 2016-10-14 | 2018-04-24 | 复旦大学 | A kind of preparation method of orixine, halofuginone hydrobromide key chiral piperidine intermediate |
| CN107954923B (en) * | 2016-10-14 | 2021-07-02 | 复旦大学 | Preparation method of key chiral piperidine intermediate of dichroine and halofuginone |
| CN108299545A (en) * | 2017-01-12 | 2018-07-20 | 复旦大学 | A method of preparing Symplocin A and its epimer |
| CN108299545B (en) * | 2017-01-12 | 2021-07-02 | 复旦大学 | Method for preparing Symplocin A and epimer thereof |
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