CN110357940A - Ao Puzuo meter synthesising process research - Google Patents
Ao Puzuo meter synthesising process research Download PDFInfo
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- CN110357940A CN110357940A CN201910711180.7A CN201910711180A CN110357940A CN 110357940 A CN110357940 A CN 110357940A CN 201910711180 A CN201910711180 A CN 201910711180A CN 110357940 A CN110357940 A CN 110357940A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
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Abstract
The invention discloses the synthetic methods of Ao Puzuo meter a kind of, on the one hand can shorten synthetic route by this method, on the other hand can greatly improve the yield and purity of target product.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the research of Ao Puzuo meter synthesis technology.
Background technique
Ao Puzuo meter (oprozomib, ONX-0912) is a kind of orally available irreversible proteasome inhibitor, tool
There are three peptide epoxy ketone structures, entitled O- methyl-N- [(2- methyl-5-thiazole base) the carbonyl]-L- seryl-O- methyl-N- of chemistry
[(1S) -2- [(2R) -2- methyl -2- Oxyranyle] -2- oxo -1- (benzyl) ethyl]-L- silk amide (O-
Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-
Methyl-2-oxiranyl] -2-oxo-1- (phenylmethyl) ethyl]-L-serinamide), for treating blood system
System malignant tumour, especially Huppert's disease (multiple myeloma, MM), are currently in III phase clinical stage.
Oprozomib is considered as the oral analog of Carfilzomib, can induce the MM Apoptosis to bortezomib drug resistant,
Observe that its effect is suitable with Carfilzomib in mice xenograft model.One Ib/II clinical trial phase has evaluated
The treatment of oprozomib Combined with Dexamethasone at least received 1 ~ 5 kind of therapeutic scheme, including lenalidomide and (or)
The recurrence of bortezomib for treating and the curative effect of intractable MM patient, as a result, it has been found that 12 can assess in patient and have 5 acquisitions
Part is alleviated, Overall response rate 41.7%.Another multicenter Ib/II clinical trial phase has evaluated oprozomib joint pool horse
Spend the curative effect of 31 RRMM patients of amine and dexamethasone in treatment, these patients used bortezomib and lenalidomide (or
Thalidomide) treatment, as a result, it has been found that about 50% patient obtains part alleviation or better curative effect, prompt oprozomib connection
Closing pomalidomide and dexamethasone in treatment has significant anti-tumor activity to RRMM, and can be resistant to well by patient.Pass through
Former patent synthetic route is retrieved, it is optimized in we, shortens to the reaction of 6 steps from the reaction of 8 steps.Using used in the present invention
Synthesis condition and method can greatly improve the yield and purity of target product.
Summary of the invention
The present invention synthesizes oprozomib using following route:
The synthesis condition of intermediate compound I are as follows:
The methyl-L-serine of protection is added in methanol, -10o10 min are stirred under C to be allowed to sufficiently be pre-chilled.Then by dichloro
Sulfoxide is slowly dropped in reaction system.The reaction was continued after completion of dropwise addition 10 min, are transferred to room temperature for reaction, reacted
Night, TLC monitoring reaction.20 mL methylene chloride are added after being directly concentrated under reduced pressure after fully reacting, are concentrated under reduced pressure repeatedly twice,
It is spin-dried for solvent, is dried in vacuo to obtain intermediate compound I, can be directly used for reacting in next step without further purification.
The synthesis condition of intermediate II are as follows:
Under ice-water bath, the methyl-L-serine of protection is dissolved in organic solvent S, and the condensing agent being then added continues stirring 30
min.Intermediate compound I is then added, addition DIPEA then reacts at room temperature 6 h after reacting 10 min.Reaction solution successively uses 0.4N HCl
Solution, 5% sodium bicarbonate and saturated common salt water washing, organic phase are dry, are concentrated to give that white solid II is not purified to be directly used in
In next step.
Wherein, condensing agent used is HOBT, PyBOP, TBTU, TATU, NHS, EDCI, and preferably HOBT and EDCI are combined.
Organic solvent S is methylene chloride, dichloroethanes, DMF, dimethyl sulfoxide, ether, toluene and tetrahydrofuran, and preferred solvent is
Methylene chloride and tetrahydrofuran, most preferred solvent are methylene chloride.
The synthesis condition of intermediate III are as follows:
Intermediate II is dissolved in methylene chloride, trifluoroacetic acid is added dropwise at -5 DEG C, and the reaction was continued under -5 °C, and TLC detection is anti-
20 min are concentrated after answering after room temperature concentration and with oil pump in room temperature.- 5oCold methyl tertiary butyl ether(MTBE) is added under C, acutely
Stirring precipitates crystal, and the solid was filtered, washs solid with cold methyl tertiary butyl ether(MTBE), solid is by being dried to obtain intermediate III
It is directly used in next step.
The synthesis condition of intermediate compound IV are as follows:
Under ice-water bath, 2- methyl thiazole-5-carboxyl acid is dissolved with methylene chloride, a certain amount of HOBT is then added, stirs five points
EDCI is added portionwise after clock, continues to stir 30 min.Intermediate III is then added, DIPEA is added with rear chamber after reacting 10 min
6 h of temperature reaction.Reaction solution successively uses 0.4N HCl solution, 5% sodium bicarbonate and saturated common salt water washing, and organic phase is dry, dense
Contracted column, obtains white solid IV.
The synthesis condition of intermediate V are as follows:
Under ice-water bath, intermediate compound I is dissolved in methanol, is slowly added to LiOH aqueous solution, continues thereafter with 10 min of stirring.Slowly
It is warmed to room temperature, is stirred at room temperature 2 hours.After fully reacting, reaction solution revolving removes methanol, and remaining water phase extracts two with ether
It is secondary.It is 2 ~ 3 that hydrochloric acid to pH value, which is added dropwise, in water phase, and ethyl acetate extraction, organic phase is dry, is concentrated to give white product V.
The synthesis condition of intermediate VI are as follows:
Under ice-water bath, (S) -2-amino-1- ((R) -2-methyloxiran-2-yl) -3- is dissolved with methylene chloride
Phenylpropan-1-one, is then added a certain amount of HOBT, and stirring is added portionwise EDCI after five minutes, continues stirring 30
min.Intermediate V is then added, addition DIPEA then reacts at room temperature 6 h after reacting 10 min.Reaction solution successively uses 0.4N HCl
Solution, 5% sodium bicarbonate and saturated common salt water washing, organic phase is dry, and concentrated column obtains white solid VI.
Specific embodiment
The present invention is further explained in the light of specific embodiments:
It weighs boc-protected methyl-L-serine (1 g, 4.6 mM) to be added in 30 mL methanol, -10o20 min are stirred under C to be made
Abundant pre-cooling.Then thionyl chloride (5.4 g, 45.6 mM) is slowly dropped in reaction system, 1 h is dripped off.Knot is added dropwise
Reaction is transferred to room temperature by the reaction was continued after beam 30 min, reaction overnight, TLC monitoring reaction.It is directly depressurized after fully reacting dense
Add 20 mL methylene chloride after contracting, be concentrated under reduced pressure repeatedly twice, be spin-dried for solvent, be dried in vacuo intermediate compound I be 760mg, receive
Rate 98%.Product can be directly used for reacting in next step without further purification.
The boc-protected methyl-L-serine of Weigh Compound (980mg, 4.5 mM) is dissolved in methylene chloride (20mL), so
After HOBT(600mg, 4.5 mmol is added), stir 10 min under -5 °C.Then EDCI(1.3 g, 6.7mmol is added portionwise),
React 30 min.Then 760mg intermediate compound I is added, is slowly added to DIPEA(1.7 g, 13.4 mmol after reacting 10 min),
It is transferred to room temperature after the reaction was continued 30 min, reacts 6h.Reaction solution uses 0.4N HCl(40 respectively after TLC monitoring fully reacting
ML), 5% NaHCO3The washing of (20 mL) and saturated salt solution (20 mL), organic phase anhydrous sodium sulfate is dry, evaporated under reduced pressure
It is 1.3g, yield 87% that solvent, which obtains intermediate II,.Product is not purified, is directly used in next step.
Intermediate II (1.3 g, 3.9 mmol) is dissolved in DCM (30 mL), trifluoroacetic acid is added dropwise at -5 DEG C
10 mL+DCM (10 mL), and 2 h are reacted under -5 °C, TLC detection is used in combination after (25 °C) of room temperature concentrations after completion of the reaction
Oil pump is in (25 °C) 20 min of concentration of room temperature.Pre-cooling 100 mL of methyl tertiary butyl ether(MTBE), stirring 10 mins analysis are added under -5 °C
Crystal out, the solid was filtered, washs solid with cold methyl tertiary butyl ether(MTBE) (20 mL), vacuum drying solid obtains intermediate III
(1.2 g, 90%)
It weighs 2- methyl thiazole-5-carboxyl acid (500mg, 3.5 mM) to be dissolved in methylene chloride (20 mL), HOBT is then added
(470mg, 3.5 mmol) stir 10 min under -5 °C.Then EDCI(1g, 5.2mmol is added portionwise), react 30 min.So
After add 1.2 g intermediate IIIs, be slowly added to DIPEA(1.4 g, 10.5 mmol after reacting 10 min), the reaction was continued 30
It is transferred to room temperature after min, reacts 6h.Reaction solution uses 0.4N HCl(40 mL respectively after TLC monitoring fully reacting), 5%
NaHCO3The washing of (20 mL) and saturated salt solution (20 mL), organic phase anhydrous sodium sulfate is dry, and evaporated under reduced pressure solvent is through column
Isolate and purify intermediate compound IV be 1.1 g, yield 86%.
Under ice-water bath, intermediate compound IV (200 mg, 0.56 mmol) is dissolved in methanol (20 mL), weighs a hydronium(ion)
Lithia (32.9 mg, 0.78 mmol) is dissolved in 5 mL water, is slowly added dropwise into reaction solution, is then slowly increased to reaction
Room temperature reacts 3h at room temperature.After TLC monitors fully reacting, reaction solution is rotated and removes methanol, remaining water phase adds 20 mL
Water is extracted twice with ether (20 mL × 2).It is 2 ~ 3 that hydrochloric acid to pH value, which is added dropwise, in remaining water phase, ethyl acetate extraction (20 mL ×
3), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate is dry, and being concentrated to give white product II is 184 mg, yield 95%.1H
NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.15 (s, 2H), 4.75 – 4.53 (m, 1H),
4.35 – 4.17 (m, 1H), 3.54 – 3.48 (m, 2H), 3.40 – 3.32 (m, 2H), 3.10 (dd, J 1 =
7.9, J 2 = 4.6 Hz, 6H), 2.38(s, 3H).
(S) -2-amino-1- ((R) -2-methyloxiran-2-yl) -3-phenylpropan-1-one is weighed, (100 mg,
0.33 mmol) it is dissolved in methylene chloride (20 mL), HOBT(44.6mg, 0.33 mmol is then added), 10 are stirred under -5 °C
min.Then EDCI(96 mg, 0.5 mmol is added portionwise), react 30 min.Then intermediate V(114 mg is added, 0.33
Mmol), DIPEA(128mg, 0.99 mmol are slowly added to after reacting 10 min), room temperature is transferred to after the reaction was continued 30 min,
React 6h.Reaction solution uses 0.4N HCl(20 mL respectively after TLC monitoring fully reacting), 5% NaHCO3(20 mL) and saturation
Saline solution (20 mL) washing, organic phase anhydrous sodium sulfate is dry, and evaporated under reduced pressure solvent is through column separating purification final product VI
153mg, yield 87%.1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.31 – 7.11 (m, 5H),
6.86 (s, 2H), 4.91 – 4.77 (m, 1H), 4.73 – 4.62 (m, 1H), 4.52 – 4.42 (m, 1H),
3.58 – 3.49 (m, 1H), 3.42 (s, 6H), 3.38 (d, J = 5.2 Hz, 2H), 3.35 – 3.33 (m,
2H), 3.33 – 3.30 (m, 2H), 2.93 – 2.76 (m, 2H), 1.26 (s, 3H).13C NMR (100 MHz,
CDCl3) δ 207.11, 169.55, 160.40, 143.73, 143.66, 129.48, 129.40, 129.36,
128.55, 128.46, 127.12, 127.03, 71.49, 71.19, 59.29, 59.21, 59.09, 53.00,
52.93, 52.89, 52.53, 37.11, 29.68, 19.62, 16.56. HRMS (ESI): calcd for
C25H32N4O7S [M + H]+, 533.6120; found, 533.6134。
Claims (4)
1. a kind of preparation process of the synthetic method intermediate II of Yi Shazuo meter, it is characterised in that the route of the technique is as follows:
。
2. preparation process as claimed in claim 1, it is characterised in that under ice-water bath, the methyl-L-serine of protection is molten
In organic solvent S, the condensing agent being then added continues to stir 30 min, intermediate compound I is then added, is added after reacting 10 min
DIPEA then reacts at room temperature 6 h；
Reaction solution successively uses 0.4N HCl solution, 5% sodium bicarbonate and saturated common salt water washing, and organic phase is dry, is concentrated to give white
Color solid II；
Wherein condensing agent used is HOBT, PyBOP, TBTU, TATU, NHS, EDCI；
Organic solvent S is selected from methylene chloride, dichloroethanes, DMF, dimethyl sulfoxide, ether, toluene and tetrahydrofuran.
3. preparation process as claimed in claim 2, it is characterised in that condensing agent is HOBT and EDCI.
4. preparation process as claimed in claim 2, it is characterised in that organic solvent S is methylene chloride or tetrahydrofuran.
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| CN201910711180.7A CN110357940A (en) | 2019-08-02 | 2019-08-02 | Ao Puzuo meter synthesising process research |
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| CN201910711180.7A CN110357940A (en) | 2019-08-02 | 2019-08-02 | Ao Puzuo meter synthesising process research |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113018415A (en) * | 2021-03-17 | 2021-06-25 | 遵义医科大学 | Novel pharmaceutical composition and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140113855A1 (en) * | 2012-10-24 | 2014-04-24 | Onyx Therapeutics, Inc. | Modified Release Formulations for Oprozomib |
| CN105949279A (en) * | 2016-04-27 | 2016-09-21 | 浙江大学 | Method for preparing proteasome inhibitor Oprozomib and analogs thereof |
| WO2017211818A1 (en) * | 2016-06-06 | 2017-12-14 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Proteasome inhibitors |
-
2019
- 2019-08-02 CN CN201910711180.7A patent/CN110357940A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140113855A1 (en) * | 2012-10-24 | 2014-04-24 | Onyx Therapeutics, Inc. | Modified Release Formulations for Oprozomib |
| CN104968650A (en) * | 2012-10-24 | 2015-10-07 | 欧尼斯治疗公司 | Modified release formulations for oprozomib |
| CN105949279A (en) * | 2016-04-27 | 2016-09-21 | 浙江大学 | Method for preparing proteasome inhibitor Oprozomib and analogs thereof |
| WO2017211818A1 (en) * | 2016-06-06 | 2017-12-14 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Proteasome inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| 段希焱: "《有机合成反应及路线设计研究》", 31 July 2019, 中国原子能出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113018415A (en) * | 2021-03-17 | 2021-06-25 | 遵义医科大学 | Novel pharmaceutical composition and application thereof |
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