CN102690231A - 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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- 238000000034 method Methods 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 7
- 229940079593 drug Drugs 0.000 title claims abstract description 6
- 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 24
- 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 compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- 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
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 abstract description 5
- 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 2
- 238000002360 preparation method Methods 0.000 description 11
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 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 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 2
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 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
- OYVLMTSYPTUNCO-XVKPBYJWSA-N CC(C)[C@@H](C(N[C@@H](C)C(ON(C(CC1)=O)C1=O)=O)=O)O Chemical compound CC(C)[C@@H](C(N[C@@H](C)C(ON(C(CC1)=O)C1=O)=O)=O)O OYVLMTSYPTUNCO-XVKPBYJWSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 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
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- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000003340 mental effect Effects 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
- 230000001537 neural effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 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
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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 compound method of alzheimer's disease potential drug Sima Seat.
(2) technical background
Alzheimer's disease (Alzheimers disease AD) is a kind of nerve degenerative diseases that carries out sexual development, and clinical manifestation is that memory and cognition dysfunction constantly increase the weight of, and carrying out property of activity of daily living goes down, and with neural mental 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 old man's morbidity is up to 50% more than 95 years old.The pathophysiological mechanism that AD is definite is not illustrated as yet fully; But existing numerous researchs show; The excessive generation of amyloid-beta and abnormal accumulation are the major causes that causes AD patient's neuronal death, in the incidence and development of AD, play a part very importantly, thereby also are the emphasis that present AD prevents and treats drug research to A β metabolism and the medicament research and development of assembling relevant target spot; Wherein the research of A β synthetic key enzyme inhibitors of gamma-secretase is paid attention to most, and progress rapidly.
Si Maxite is the inhibitors of gamma-secretase of Lilly Co., Eli.'s exploitation, is in extensive III phase clinical stage at present.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 in heptan-1-base is amino)-1-carbonyl propane-2-yl) yulocrotine.Its chemical structural formula is following:
WO02040508; US2007299053A1 etc. disclose the compound method of Si Maxite, and this method is with (S)-1-amino-3-methyl-4, and 5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone is to obtain (S)-2-amino-N-((S)-3-methyl-2-carbonyl-2 behind the L-L-Ala condensation deprotection of raw material and BOC protection; 3; 4,5-tetrahydrochysene-1H-benzo [d] a word used for translation English in heptan-1-yl) propionic acid amide, condensation obtains Si Maxite with L-Alpha-hydroxy isovaleric acid again.Concrete route is following:
The starting raw material that this route is used (S)-1-amino-3-methyl-4,5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone CAS registration number is 253324-92-4, needs chiral separation, costs an arm and a leg.Above-mentioned route with the raw material of costliness as initial after three-step reaction makes product, can consume a large amount of raw materials, increased cost.Final step makes through the DCC condensation, and impurity such as the DCU that generates in the reaction process are difficult to remove, and has increased the difficulty of purifying.
(3) summary of the invention
The earlier synthetic side chain fragment of design route of the present invention after the OSu activation again with (S)-1-amino-3-methyl-4,5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-reactive ketone makes Si Maxite.
Concrete steps are to be that raw material and L-Alpha-hydroxy isovaleric acid (2) condensation obtain midbody (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3) with L-alanine methyl ester (1); 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; Last with (S)-1-amino-3-methyl-4,5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone (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 in heptan-2 (3H)-ketone, thus reduced cost.
(2) adopt right-COOH to carry out the OSu activation and replace the DCC condensation, improved productive rate, reduced the difficulty of purifying.
(3) through to side chain segmental quality control can better control product gas purity.
Concrete route is following:
(4) embodiment
Through specific embodiment this invention is done further to describe below.
Embodiment one
The first step: the preparation of midbody (S)-methyl (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3)
In the 500mL there-necked flask, add L-alanine methyl ester (1) 10.0g, L-Alpha-hydroxy isovaleric acid (2) 11.5g, N, N '-NSC 57182 24.0g all mixes the back and adds methylene dichloride 200mL, stirring reaction under the room temperature.The TLC detection reaction finishes the back stopped reaction; Add the dilution of 100mL ETHYLE ACETATE after revolving dried organic solvent; Remove by filter insolubles, use 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 midbody (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,, add sodium hydroxide 1g with 5mL water and 20mL dissolve with ethanol; Add the reaction solution stirring at room, question response finishes the back and regulates pH to neutral with the hydrochloric acid of 0.5mol/LHCl, revolves dried solvent; Steam residual with anhydrous alcohol solution; Filter, get filtrating and revolve the dried product 4.4g that obtains, productive rate 96%.
The 3rd step: (S)-preparation of 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5)
In the 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 '-NSC 57182 6.5g all mixes the back and adds methylene dichloride 52mL, stirring reaction under the room temperature.The TLC detection reaction finishes the back stopped reaction; Add the dilution of 50mL ETHYLE ACETATE after revolving dried organic solvent; Remove by filter insolubles, use 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 4th step: the preparation of Si Maxite
In the 50ml reaction flask, add (S)-1-amino-3-methyl-4; 5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone (7) 1.0g with (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) 1.5g; Add methylene dichloride 25ml dissolving; Reaction solution room temperature reaction, TLC detection reaction finish the back stopped reaction.Reaction solution is used 0.1mol/LHCl, and organic solvent is revolved in saturated sodium bicarbonate solution and saturated sodium-chloride washing 2-3 time, and the gained bullion obtains Si Maxite 1.7g productive rate 91% through the mixture recrystallization of methyl alcohol and ether.
Embodiment two
The first step: the preparation of midbody (S)-methyl (S)-methyl 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic ester (3)
According to the first step method preparation among the embodiment one.
Second step: the preparation of midbody (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid (4)
According to second one step process preparation among the embodiment one.
The 3rd step: (S)-preparation of 2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5)
According to the 3rd one step process preparation among the embodiment one.
The 3rd step: the preparation of Si Maxite
In the 50ml reaction flask, add (S)-1-amino-3-methyl-4; 5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone (7) 1.0g with (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) 2.2g; Add THF 25ml dissolving; Reaction solution adds 50 degree reactions, and the TLC detection reaction finishes the back stopped reaction.Reaction solution is used 0.1mol/LHCl, and organic solvent is revolved in saturated sodium bicarbonate solution and saturated sodium-chloride washing 2-3 time, and the gained bullion obtains Si Maxite 1.8g productive rate 96% through the mixture recrystallization of methyl alcohol and ether.
Claims (3)
1. compound method of treating alzheimer's disease potential drug Sima Seat, its step is following:
2. the compound method of Sima Seat according to claim 1; It is characterized in that the synthetic of Si Maxite is via midbody (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) and midbody (S)-1-amino-3-methyl-4,5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone 1.0g (7) reaction makes.
3. according to step described in the claim 2; It is characterized in that reacting used midbody (S)-1-amino-3-methyl-4, the mol ratio of 5-dihydro-1H-benzo [d] a word used for translation English in heptan-2 (3H)-ketone 1.0g (7) and midbody (S)-2-((S)-2-hydroxy-3-methyl butyrylamino) propionic acid-OSu (5) is 1: 1-1: 1.5; Solvent for use is a methylene dichloride, chloroform, THF, methyl alcohol, ethanol; Used temperature is the 0-90 degree.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2002040508A2 (en) * | 2000-11-17 | 2002-05-23 | Eli Lilly And Company | Lactam dipeptide and its use in inhibiting beta-amyloid peptide release |
| CN1486184A (en) * | 2000-11-17 | 2004-03-31 | 伊莱利利公司 | Lactam compound to inhibit beta-amyloid peptide release or synthesis |
| CN1575282A (en) * | 2000-11-17 | 2005-02-02 | 伊莱利利公司 | Lactam compound |
| WO2009012734A2 (en) * | 2007-07-25 | 2009-01-29 | Zentiva A.S. | New salts of bazedoxifene |
| US20110306596A1 (en) * | 2009-07-27 | 2011-12-15 | Auspex Pharmaceuticals, Inc. | Benzazepine inhibitors of gamma-secretase |
-
2012
- 2012-04-11 CN CN201210103699.5A patent/CN102690231B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2002040508A2 (en) * | 2000-11-17 | 2002-05-23 | Eli Lilly And Company | Lactam dipeptide and its use in inhibiting beta-amyloid peptide release |
| CN1486184A (en) * | 2000-11-17 | 2004-03-31 | 伊莱利利公司 | Lactam compound to inhibit beta-amyloid peptide release or synthesis |
| CN1575282A (en) * | 2000-11-17 | 2005-02-02 | 伊莱利利公司 | Lactam compound |
| WO2009012734A2 (en) * | 2007-07-25 | 2009-01-29 | Zentiva A.S. | New salts of bazedoxifene |
| US20110306596A1 (en) * | 2009-07-27 | 2011-12-15 | Auspex Pharmaceuticals, Inc. | Benzazepine inhibitors of gamma-secretase |
Non-Patent Citations (4)
| Title |
|---|
| PING YI,等: "Disposition and Metabolism of Semagacestat, a -Secretase Inhibitor, in Humans", 《DRUG METABOLISM AND DISPOSITION》 * |
| YANGWEI JOHN PU,等: "A Practical Method for Functionalized Peptide or Amide Bond Formation in Aqueous−Ethanol Media with EDC as Activator", 《ORG. PROCESS RES. DEV.》 * |
| YANGWEI JOHN PU,等: "A Practical Method for Functionalized Peptide or Amide Bond Formation in Aqueous−Ethanol Media with EDC as Activator", 《ORG. PROCESS RES. DEV.》, vol. 13, no. 2, 4 December 2008 (2008-12-04), pages 310 - 314 * |
| 范鸣: "阿尔茨海默病治疗药Semagacestat", 《药学进展》 * |
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Denomination of invention: Synthesis of a potential drug for Alzheimer's disease Effective date of registration: 20201229 Granted publication date: 20140709 Pledgee: Bank of Jiangsu Limited by Share Ltd. Taishan Nanjing road subbranch Pledgor: ACESYS PHARMATECH Ltd. Registration number: Y2020980010244 |
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