CN102690231B - Method for synthesizing potential drug of Semagacestat for treating Alzheimer disease - Google Patents
Method for synthesizing potential drug of Semagacestat for treating Alzheimer disease Download PDFInfo
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- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 7
- 229940079593 drug Drugs 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title abstract description 9
- PKXWXXPNHIWQHW-RCBQFDQVSA-N (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide Chemical compound C1CN(C)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](O)C(C)C)C2=CC=CC=C21 PKXWXXPNHIWQHW-RCBQFDQVSA-N 0.000 title abstract 3
- 229950001900 semagacestat Drugs 0.000 title abstract 3
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 11
- 238000013519 translation Methods 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- 238000009833 condensation Methods 0.000 abstract description 7
- 230000005494 condensation Effects 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- NGEWQZIDQIYUNV-BYPYZUCNSA-N (S)-2-hydroxy-3-methylbutyric acid Chemical compound CC(C)[C@H](O)C(O)=O NGEWQZIDQIYUNV-BYPYZUCNSA-N 0.000 abstract description 6
- NGEWQZIDQIYUNV-UHFFFAOYSA-N L-valinic acid Natural products CC(C)C(O)C(O)=O NGEWQZIDQIYUNV-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012634 fragment Substances 0.000 abstract description 3
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 11
- OXNBDTKGTGHILO-WDSKDSINSA-N (2S)-2-[[(2S)-2-hydroxy-3-methylbutanoyl]amino]propanoic acid Chemical compound O[C@H](C(=O)N[C@H](C(=O)O)C)C(C)C OXNBDTKGTGHILO-WDSKDSINSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- -1 ALANINE methyl esters Chemical class 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 2
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 230000007324 Aβ metabolism Effects 0.000 description 1
- XOGYNDDLZHMHBS-BQBZGAKWSA-N CC(C)[C@@H](C(N[C@@H](C)C(OC)=O)=O)O Chemical compound CC(C)[C@@H](C(N[C@@H](C)C(OC)=O)=O)O XOGYNDDLZHMHBS-BQBZGAKWSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
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- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
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- 230000008289 pathophysiological mechanism Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
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- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizinga potential drug of Semagacestat for treating Alzheimer disease. The method comprises the steps of using L-alanine methyl ester and L-alpha- hydroxy isovaleric acid as raw materials, synthesizing the raw materials into side chain fragments, allowing the side chain to be activated by OSu, and carrying out condensation with (S)-1-amino-3-methyl-4,5-dihydrogen-1H-benzo[d]azepin-2(3H)-one to obtain Semagacestat. The method has the advantages of mild reaction conditions, simple operation process, low cost, and high yield.
Description
(1) technical field
The invention belongs to technical field of medicine synthesis, particularly, the present invention relates to treat the synthetic method of alzheimer's disease potential drug Sima Seat.
(2) technical background
Alzheimer's disease (Alzheimers disease, AD) be a kind of nerve degenerative diseases that carries out sexual development, clinical manifestation is that memory and cognition dysfunction constantly increases the weight of, and carrying out property of activity of daily living goes down, and with neuropsychic symptom and behavior disorder.AD is the most common dull-witted type, and over-65s elderly population morbidity is 13%, and its sickness rate significantly raises with age growth, and more than 95 years old old man morbidity is up to 50%.The pathophysiological mechanism that AD is definite is illustrated not yet completely; but existing numerous research shows; the excessive generation of amyloid-beta and abnormal accumulation are the major causes that causes AD patient's neuronal death; in the developing of AD, play a part very important; thereby be also the emphasis of current AD control drug research for A β metabolism and the medicament research and development of assembling relevant target spot; wherein the research of the synthetic key enzyme inhibitors of gamma-secretase of A β is paid attention to most, and progress rapidly.
Si Maxite is the inhibitors of gamma-secretase of Lilly Co., Eli.'s exploitation, at present in extensive III phase clinical stage.Si Maxite chemistry (S)-2-hydroxy-3-methyl-N-by name ((S)-1-((S)-3-methyl-2-carbonyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] a word used for translation English-1-in heptan base amino)-1-carbonyl propane-2-yl) butyramide.Its chemical structural formula is as follows:
WO02040508; US2007299053A1 etc. disclose the synthetic method of Si Maxite; the method is with (S)-1-amino-3-methyl-4; 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one is to obtain (S)-2-amino-N-((S)-3-methyl-2-carbonyl-2 after the ALANINE condensation deprotection of raw material and BOC protection; 3; 4; 5-tetrahydrochysene-1H-benzo [d] a word used for translation English-1-in heptan yl) propionic acid amide, then condensation obtains Si Maxite with L-Alpha-hydroxy isovaleric acid.Concrete route is as follows:
Starting raw material (S)-1-amino-3-methyl-4 that this route is used, 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one CAS registration number is 253324-92-4, needs chiral separation, expensive.Above-mentioned route makes product through three-step reaction using expensive raw material after initial, can consume a large amount of raw materials, has increased cost.Final step makes by DCC condensation, and the impurity such as the DCU generating in reaction process are difficult to remove, and has increased the difficulty of purifying.
(3) summary of the invention
Design route of the present invention first synthetic side chain fragment after OSu activation again with (S)-1-amino-3-methyl-4,-one reaction in 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H) makes Si Maxite.
Concrete steps are taking ALANINE methyl esters (1) as raw material and L-Alpha-hydroxy isovaleric acid (2) condensation obtains intermediate (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3), obtain (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid (4) through hydrolysis again and obtain (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) with N-maloyl imines (6) condensation, finally with (S)-1-amino-3-methyl-4, 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one (7) reaction makes Si Maxite.
Beneficial effect:
(1) reduced (S)-1-amino-3-methyl-4, the consumption of 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one, thus reduce cost.
(2) adopt p-COOH to carry out OSu activation and replace DCC condensation, improved productive rate, reduced the difficulty of purifying.
(3) by can better control the purity of product to the quality control of side chain fragment.
Concrete route is as follows:
(4) embodiment
Below by specific embodiment, this invention is further described.
Embodiment mono-
The first step: the preparation of intermediate (S)-methyl (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3)
In 500mL there-necked flask, add ALANINE methyl esters (1) 10.0g, L-Alpha-hydroxy isovaleric acid (2) 11.5g, N, N '-dicyclohexylcarbodiimide 24.0g, adds methylene dichloride 200mL, stirring reaction under room temperature after all mixing.TLC detection reaction finishes rear stopped reaction, after being spin-dried for organic solvent, add the dilution of 100mL ethyl acetate, remove by filter insolubles, with 0.1mol/LHCl, saturated sodium bicarbonate solution and saturated sodium-chloride washing 2-3 time, obtain (S)-methyl (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3) 17.3g, productive rate 88%.
Second step: the preparation of intermediate (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid (4)
In 100mL single port bottle, add (S)-methyl (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3) 5.0g, with 5mL water and 20mL dissolve with ethanol, add sodium hydroxide 1g, add reaction solution stirring at room temperature, question response finishes the rear salt acid for adjusting pH with 0.5mol/LHCl to neutral, is spin-dried for solvent, residual with anhydrous alcohol solution steaming, filter, get filtrate being spin-dried for and obtain product 4.4g, productive rate 96%.
The 3rd step: the preparation of (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5)
In 100mL there-necked flask, add (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid (4) 5.0g, N-maloyl imines (6) 3.0g, N, N '-dicyclohexylcarbodiimide 6.5g, after all mixing, add methylene dichloride 52mL, stirring reaction under room temperature.TLC detection reaction finishes rear stopped reaction, after being spin-dried for organic solvent, add the dilution of 50mL ethyl acetate, remove by filter insolubles, with 0.1mol/LHCl, saturated sodium bicarbonate solution and saturated sodium-chloride washing 2-3 time, obtain (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) 6.2g, productive rate 82% through recrystallization from ethyl acetate/petroleum ether
The preparation of the 4th step: Si Maxite
In 50ml reaction flask, add (S)-1-amino-3-methyl-4,5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one (7) 1.0g and (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) 1.5g, add methylene dichloride 25ml to dissolve, reaction solution room temperature reaction, TLC detection reaction finishes rear stopped reaction.By reaction solution use 0.1mol/LHCl, saturated sodium bicarbonate solution and saturated sodium-chloride washing 2-3 time, revolve organic solvent, and gained crude product, through the mixture recrystallization of methyl alcohol and ether, obtains Si Maxite 1.7g productive rate 91%.
Embodiment bis-
The first step: the preparation of intermediate (S)-methyl (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3)
According to the first step method preparation in embodiment mono-.
Second step: the preparation of intermediate (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid (4)
According to second step method preparation in embodiment mono-.
The 3rd step: the preparation of (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5)
According to the 3rd one step process preparation in embodiment mono-.
The preparation of the 3rd step: Si Maxite
In 50ml reaction flask, add (S)-1-amino-3-methyl-4,5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one (7) 1.0g and (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) 2.2g, add tetrahydrofuran (THF) 25ml to dissolve, reaction solution adds 50 degree reactions, and TLC detection reaction finishes rear stopped reaction.By reaction solution use 0.1mol/LHCl, saturated sodium bicarbonate solution and saturated sodium-chloride washing 2-3 time, revolve organic solvent, and gained crude product, through the mixture recrystallization of methyl alcohol and ether, obtains Si Maxite 1.8g productive rate 96%.
Claims (3)
1. a synthetic method for the treatment of alzheimer's disease potential drug Sima Seat, its step is as follows:
2. the synthetic method of Sima Seat according to claim 1, it is characterized in that the synthetic of Si Maxite is via the intermediate as shown in chemical formula 5 (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-succimide base and the intermediate as shown in chemical formula 7 (S)-1-amino-3-methyl-4,-one reaction in 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H) makes.
3. according to the synthetic method of the Si Maxite in claim 2, it is characterized in that intermediate (S)-1-amino-3-methyl-4 as shown in chemical formula 7 used in reaction, the mol ratio of 5-dihydro-1H-benzo [d] a word used for translation English-2 in heptan (3H)-one and the intermediate as shown in chemical formula 5 (S)-2-((S) 2-hydroxy-3-methyl butyrylamino) propionic acid-succimide base is 1: 1-1: 1.5; Solvent for use is methylene dichloride, chloroform, tetrahydrofuran (THF), methyl alcohol, ethanol; Temperature used is 0-90 degree.
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| WO2002040508A2 (en) * | 2000-11-17 | 2002-05-23 | Eli Lilly And Company | Lactam dipeptide and its use in inhibiting beta-amyloid peptide release |
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| US20110306596A1 (en) * | 2009-07-27 | 2011-12-15 | Auspex Pharmaceuticals, Inc. | Benzazepine inhibitors of gamma-secretase |
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| US20020045747A1 (en) * | 1996-12-23 | 2002-04-18 | Jing Wu | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds |
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