CN108640886A - A kind of synthetic method of the inhibitor BMS-708163 generated as beta amyloid peptide - Google Patents
A kind of synthetic method of the inhibitor BMS-708163 generated as beta amyloid peptide Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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Abstract
The invention discloses the synthesis technologies of anti HIV-1 virus drug candidate BMS 708163 a kind of.The process route is novel, and step is short, and reaction yield is high, and production cost is low, has larger implementary value and economic results in society.The route of the technique is as follows.
Description
Technical field
Field of the present invention belongs to pharmaceutical synthesis field, and in particular to a kind of inhibitor BMS- generated as beta amyloid peptide
708163 synthesis technology.
Background technology
Alzheimer's disease is commonly called as Alzheimer, be a kind of Development process slowly, with continuing of constantly deteriorating of time
Nerve dysfunction, the real origin cause of formation is still unknown so far.But, have studies have shown that this neurodegenerative disease with
Two kinds of albumen of abnormal accumulation are related in the brain：Tau albumen and beta-amyloid protein.The deduction of most mainstream is：Beta amyloid
Albumen is accumulated at first, is caused neuronal synapse dysfunction, Tau protein hyperphosphorylations and secondary inflammatory reaction, is led to nerve
Member denaturation is dead, to swallow the functions such as memory, cognition.The study found that with age, can go out in the brain of some people
The accumulation of existing beta-amyloid protein patch, hippocampus body region of this patch in Alzheimer Disease patient（Study and memory work(
It can be related）It is particularly abundant.Therefore, it is targeting that most of clinical test at present, which is with beta-amyloid protein, it is intended to decomposition or resistance
The only formation of beta-amyloid protein patch.
BMS-708163 is developed by Bristol Myers Squibb, can selectively block the processing of the APP substrates of enzyme, relatively
Save Notch processing.Notch is a kind of transmembrane receptor, signal transduction intestinal cell destiny is determined and lymphocyte at
It is ripe to be important.In preclinical models, Notch works as the tumor inhibitor in skin.Notch inhibition is believed to
Lead to side effect, the pervious clinical compounds semagacestat of forced termination；Therefore, subsequent drug development program is intended to reality
The separation of bigger between existing APP and Notch inhibits.Studies have shown that BMS-708163 in cell culture to the selectivity of APP ratio
To 137 times of the high selectivity of Notch, and CSFA β levels can be steadily reduced, without causing in rat and dog
Notch is xicity related.
Patent CN102718689A discloses a kind of preparation method of BMS-708163.By compound 1 under basic conditions
It is reacted with parachloroben-zenesulfonyl chloride 2, compound 5 then is obtained by the reaction with the fluoro- 4- cyano benzyl bromines of 2- 4.Compound 5 and azanol is anti-
It should obtain compound 6.Compound 6 with trimethyl orthoformate under the action of Lewis acid through being obtained by the reaction target compound BMS-
708163.Detailed reaction See Figure reaction equation.This method, which uses, has intense irritation and aggressive reagent boron trifluoride
Ether, there are the shortcomings of complicated for operation, yield is low, purification difficult.
Invention content
In view of this, big in order to solve existing BMS-708163 difficulty of preparation technology, loss is more, is not easy to realize industrialized
Disadvantage, the present invention provide a kind of new preparation method, and this method simple process, raw material is cheap and easy to get, high income, safe,
It is suitble to industrial production.
The method for preparing BMS-708163 of the present invention includes that steps are as follows：
1. compound 7 is restored by DIBAl-H, compound 8 is made；
2. compound 8, by asymmetric reduction amination, obtains compound 10 with compound 9；
3. target compound BMS-708163 is obtained by the reaction with parachloroben-zenesulfonyl chloride 2 in compound 10.
The synthesis condition of compound 8 is：
Compound 7 and DIBAl-H are mixed in solvent 1, stir and are cooled to -78 DEG C.After the completion of reaction, methanol is added and satisfies
And aqueous sodium potassium tartrate, after being warmed to room temperature, solvent 2 is added, after stirring 2-3 hours, gets organic phase, dry concentration obtains
To compound 8.
The mole dosage ratio of the wherein dosage of DIBAl-H and compound 7 is 1-8：1；Solvent 1 is selected from normal heptane, tetrahydrochysene
The volumetric usage ratio of furans, Isosorbide-5-Nitrae-dioxane, toluene or dichloromethane, dosage and compound 7 is 1-20：1；Methanol
The volumetric usage ratio of dosage and compound 7 is 1-20：1；It is saturated the volume of the dosage and compound 7 of aqueous sodium potassium tartrate
Amount ratio is 1-20：1；Solvent 2 be selected from normal heptane, methanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene or dichloromethane,
The volumetric usage ratio of dosage and compound 7 is 1-20：1.
The synthesis condition of compound 10 is：
By compound 8, compound 9, cat and ligand L are mixed in solvent 3, lead to hydrogen（5 atm）, heating stirring.Cooling, adds
Enter tap water, stir, filtration drying obtains compound 10.
Wherein catalyst cat is selected from [RuCl2(p-cymene)]、(PPh3)3RhCl or [PCy3Ir(COD)py]PF6, use
The mole dosage ratio of amount and compound 8 is 0.1-0.5：1；Ligand L is selected from DIOP, DuPhos, PhenPhos, BPPM, BINAP
Or DIPHEMP, the mole dosage ratio of dosage and compound 8 is 0.1-0.5：1；The dosage of compound 9 is rubbed with compound 8
Your amount ratio is 1-5：1；Solvent 3 is selected from normal heptane, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, acetonitrile or dichloromethane,
The volumetric usage ratio of its dosage and compound 8 is 1-20：1；The dosage of tap water is 1-with the volumetric usage ratio of compound 8
20：1.
The synthesis condition of target compound BMS-708163 is：
By compound 10, alkali, parachloroben-zenesulfonyl chloride 2 is mixed with solvent 4, heating stirring；Water is added, cools down, filters, it is dry, it obtains
To BMS-708163.
Wherein alkali is selected from TEA, DIPEA, potassium carbonate, sodium carbonate or DBU, and the mole dosage ratio of dosage and compound 10 is
1 – 5：1；The dosage of parachloroben-zenesulfonyl chloride 2 is 1-5 with the mole dosage ratio of compound 10：1；Solvent 4 be selected from tetrahydrofuran,
The volumetric usage ratio of Isosorbide-5-Nitrae-dioxane, 2- methyltetrahydrofurans, DCM and ethyl acetate, dosage and compound 10 is 1-
20：1；The dosage of water is 1-10 with the mole dosage ratio of compound 10：1.
Present invention process route is novel, and process conditions are simple, and reaction step is short, easy to operate, and reaction yield is high, have compared with
Big implementary value and economic results in society.
Specific implementation mode
The present invention is further explained in the light of specific embodiments, provides the implementation detail of the present invention, but not
It is intended to limit protection scope of the present invention.
Embodiment 1
（1）The preparation of compound 8
By compound 7（58.5 g, 309 mmol）And DIBAl-H（70.6 g, 618 mmol）It is mixed in DCM（300 mL）
In, it stirs and is cooled to -78 DEG C.After the completion of reaction, methanol is added（100 mL）With saturation aqueous sodium potassium tartrate（500
mL）, after being warmed to room temperature, DCM is added（1000 mL）, after stirring 2-3 hours, get organic phase, dry concentration obtains compound 8
（52.8 g, 88.4%）.
1H NMR (500 MHz, Chloroform-d) δ 9.14 (s, 1H), 7.89 (dd, J = 7.5, 1.4
Hz, 1H), 7.50 (dd, J = 8.0, 1.5 Hz, 1H), 7.46 – 7.40 (m, 1H), 3.88 (td, J =
6.8, 1.0 Hz, 2H), 3.35 (q, J = 6.7 Hz, 1H), 3.29 (q, J = 6.7 Hz, 1H); 13C NMR
(125 MHz, Chloroform-d) δ 165.5, 160.6, 153.7, 131.8, 130.4, 129.3, 122.6,
115.2, 42.3; m/z (MS-ESI): 194.27 [M + 1]+.
（2）The preparation of compound 10
By compound 8（48.4 g, 250 mmol）, compound 9（76.3 g, 451 mmol）、(PPh3)3RhCl（46.4 g,
50 mmol）With BINAP（46.8 g, 75 mmol）It is mixed in acetonitrile（260 mL）In, lead to hydrogen（5 atm）, heating stirring.
Tap water is added in cooling（2600 mL）, stir, filtration drying obtains compound 10（74.4 g, 85.8%）.
1H NMR (500 MHz, Chloroform-d) δ 9.17 (s, 1H), 7.85 (dd, J = 7.5, 1.5
Hz, 1H), 7.52 (dd, J = 8.0, 1.5 Hz, 1H), 7.46 – 7.40 (m, 1H), 7.08 (s, 1H),
4.05 – 3.93 (m, 2H), 3.58 – 3.44 (m, 2H), 2.39 – 2.25 (m, 1H), 2.25 – 2.12
(m, 1H), 1.74 – 1.57 (m, 2H); 13C NMR (125 MHz, Chloroform-d) δ: 180.1, 166.7,
160.9, 153.3, 130.5, 130.1, 126.4, 126.3, 121.2, 115.7, 67.9, 44.4, 34.2,
13.8; m/z (MS-ESI): 347.19 [M + 1]+.
（3）The preparation of BMS-708163
By compound 10（50.0 g, 144 mmol）, TEA（51.1 g, 505 mmol）, parachloroben-zenesulfonyl chloride 2（54.9 g,
260 mmol）With tetrahydrofuran（500 mL）Mixing, heating stirring；Water is added（5000 mL）, cool down, filters, it is dry, it obtains
BMS-708163（68.3 g, 90.8%）.
1H NMR (500 MHz, CDCl3) δ 1.40 - 1.58 (m, 1H), 1.75 - 1.90 (m, 1H),
1.92 - 2.07 (m, 1H), 2.10 - 2.26 (m, 1H), 4.37 (dd, J=8.67, 6.22 Hz, 1H),
4.48 (d, J=15.64 Hz, 1H), 4.64 (d, J=15.82 Hz, 1H), 5.54 (s, 1H), 6.33 (s,
1H), 7.44 - 7.54 (m, 2H), 7.62 (t, J=7.72 Hz, 1H), 7.68 - 7.76 (m, 3H), 7.85
(dd, J=7.91, 1.51 Hz, 1H), 8.76 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 170.34,
167.75, 165.80, 159.64, 138.19, 137.64, 131.25, 129.31, 129.23, 129.05,
126.74, 126.91, 126.80, 123.12, 113.7, 57.92, 41.38, 30.04, 22.90. m/z (MS-
ESI): 521.52 [M + 1]+。
Claims (4)
1. the synthetic method of compound BMS-708163, it is characterised in that the route of the technique is as follows：
2. preparation process as described in claim 1, it is characterised in that the synthesis condition of compound 8 is：
Compound 7 and DIBAl-H are mixed in solvent 1, stir and are cooled to -78 DEG C；After the completion of reaction, methanol is added and satisfies
And aqueous sodium potassium tartrate, after being warmed to room temperature, solvent 2 is added, after stirring 2-3 hours, gets organic phase, dry concentration obtains
To compound 8；
The mole dosage ratio of the wherein dosage of DIBAl-H and compound 7 is 1-8：1；
Solvent 1 is selected from normal heptane, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene or dichloromethane, the body of dosage and compound 7
Product amount ratio is 1-20：1；
The dosage of methanol is 1-20 with the volumetric usage ratio of compound 7：1；
The volumetric usage ratio of the dosage and compound 7 that are saturated aqueous sodium potassium tartrate is 1-20：1；
Solvent 2 is selected from normal heptane, methanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene or dichloromethane, dosage and compound 7
Volumetric usage ratio be 1-20：1.
3. preparation process as described in claim 1, it is characterised in that the synthesis condition of compound 10 is：
By compound 8, compound 9, cat and ligand L are mixed in solvent 3, lead to hydrogen (5atm), heating stirring；Cooling is added
Tap water, stirring, filtration drying obtain compound 10；
Wherein catalyst cat is selected from [RuCl2(p-cymene)]、(PPh3)3RhCl or [PCy3Ir(COD)py]PF6, dosage with
The mole dosage ratio of compound 8 is 0.1-0.5：1；
Ligand L is selected from DIOP, DuPhos, PhenPhos, BPPM, BINAP or DIPHEMP, dosage and compound 8 mole with
Amount is than being 0.1-0.5：1；
The dosage of compound 9 is 1-5 with the mole dosage ratio of compound 8：1；
Solvent 3 is selected from normal heptane, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, acetonitrile or dichloromethane, dosage and compound 8
Volumetric usage ratio be 1-20：1；
The dosage of tap water is 1-20 with the volumetric usage ratio of compound 8：1.
4. preparation process as described in claim 1, it is characterised in that the synthesis condition of target compound BMS-708163 is：
By compound 10, alkali, parachloroben-zenesulfonyl chloride 2 is mixed with solvent 4, heating stirring；Water is added, cools down, filters, it is dry, it obtains
To BMS-708163；
Wherein alkali is selected from TEA, DIPEA, potassium carbonate, sodium carbonate or DBU, and the mole dosage ratio of dosage and compound 10 is 1-5：
1；
The dosage of parachloroben-zenesulfonyl chloride 2 is 1-5 with the mole dosage ratio of compound 10：1；
Solvent 4 is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, 2- methyltetrahydrofurans, DCM and ethyl acetate, dosage and chemical combination
The volumetric usage ratio of object 10 is 1-20：1；
The dosage of water is 1-10 with the mole dosage ratio of compound 10：1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19933611A1 (en) * | 1999-07-17 | 2001-01-18 | Aventis Res & Tech Gmbh & Co | Process for the preparation of amines by homogeneously catalyzed reductive amination of carbonyl compounds |
| CN101910141A (en) * | 2007-10-31 | 2010-12-08 | 百时美施贵宝公司 | A novel alpha-(N-sulfonamido)acetamide compound as an inhibitor of beta amyloid peptide production |
-
2018
- 2018-08-01 CN CN201810859746.6A patent/CN108640886A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19933611A1 (en) * | 1999-07-17 | 2001-01-18 | Aventis Res & Tech Gmbh & Co | Process for the preparation of amines by homogeneously catalyzed reductive amination of carbonyl compounds |
| CN101910141A (en) * | 2007-10-31 | 2010-12-08 | 百时美施贵宝公司 | A novel alpha-(N-sulfonamido)acetamide compound as an inhibitor of beta amyloid peptide production |
Non-Patent Citations (3)
| Title |
|---|
| MICHAEL S. CHRISTODOULOU ET AL.: "Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| RENAT KADYROV ET AL.: "The First Highly Enantioselective Homogeneously Catalyzed Asymmetric Reductive Amination: Synthesis of α-N-Benzylamino Acids", 《J. ORG. CHEM.》 * |
| VITALI I. TARAROV ET AL.: "On the reductive amination of aldehydes and ketones catalyzed by homogeneous Rh(I) complexes", 《CHEM. COMMUN.》 * |
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Application publication date: 20181012 |