CN107311914A - A kind of synthetic method of the smooth intermediate of roller - Google Patents
A kind of synthetic method of the smooth intermediate of roller Download PDFInfo
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- CN107311914A CN107311914A CN201710689505.7A CN201710689505A CN107311914A CN 107311914 A CN107311914 A CN 107311914A CN 201710689505 A CN201710689505 A CN 201710689505A CN 107311914 A CN107311914 A CN 107311914A
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- compound
- anhydrous
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- smooth intermediate
- roller
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of formula（1）The synthetic method of the smooth intermediate of compound roller, by formula（2）And formula（3）As initiation material, through following series reaction, formula is finally made in compound（1）Compound, i.e., the described smooth intermediate of roller：
Description
Technical field
The present invention relates to a kind of synthetic method of the smooth intermediate of roller, belong to technical field of medicine synthesis.
Background technology
Smooth (the common name of roller：Rolapitan, trade name Varubi), chemistry is entitled: (5S,8S)-8-{
[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] methyl } } -8- phenyl -1,7- phenodiazines loop coil [4.5] certain herbaceous plants with big flowers alkane -2- ketone
Mono-hydrochloric salts monohydrate, molecular formula is：C25H26F6N2O2·HCl·H2O.The molecular weight of the smooth compound of roller：554.95；
CAS registration numbers：552292-08-7 ；Structural formula is shown in formula 1：
Formula 1
Roller is smooth to be researched and developed by Tesaro companies.The treatment adult cancer patient that September in 2015 is ratified in the U.S. on the 2nd it is initial and
Repeat the medicine of period of delay nausea and vomiting caused by chemotherapy.A kind of smooth P/ neurokinine-1s of roller（NK-1）Receptor antagonist
Agent, can activate the nausea and vomiting induced in some cancer chemotherapy medicines, and maincenter work is particularly played in period of delay nausea and vomiting
Nk 1 receptor.
Prior art literature
Non-patent literature： 1 ：Drugs, 2013, 73, 3, P249-P62；Non-patent literature 2：Curr Oncol Rep,
2016, 18, 1, P2;
Patent document：CN1606545B and CN102573475B.
In the prior art, the synthesis technique of the smooth intermediate of roller, often more complicated, cost is higher, but also exists
The low and ropy defect of product yield, it is impossible to be adapted to industrialized production.
The content of the invention
Goal of the invention：In order to overcome the deficiencies in the prior art, the invention provides a kind of smooth intermediate of roller
Synthetic method.
Technical scheme：To achieve the above object, the invention provides a kind of formula（1）The conjunction of the smooth intermediate of compound roller
Into method, by formula（2）And formula（3）As initiation material, through following series reaction, formula is finally made in compound（1）Compound,
The i.e. described smooth intermediate of roller：
。
Preferably, the compound（2）And compound（3）Compound is made through condensation reaction（4）；Compound（4）Through
Compound is made in imidization（5）；Compound（5）And compound（6）RMgBr through asymmetric 1,2- addition reaction systems
Obtain compound（7）；Final compound（7）Compound is made through deprotection-condensation reaction（1）, i.e., the described smooth intermediate of roller.
Preferably, the compound（2）And compound（3）Reaction in：Reaction dissolvent is selected from anhydrous tetrahydro furan, nothing
Water ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous acetonitrile, anhydrous tertbutyl ether, water and anhydrous
One or several kinds in 2- methyltetrahydrofurans；Reaction temperature is -20~30 DEG C；
It is used as further preferred, the compound（2）And compound（3）Mol ratio be 1:1~1.2；It is used in reaction to urge
Agent is selected from a kind of or several in copper chloride, stannous chloride, copper bromide, cuprous bromide, copper bromide dimethyl disulfide and copper cyanider
Kind；Compound（2）Mol ratio with catalyst is 200:1~20.
Preferably, the compound（4）Reaction in：Reaction dissolvent is selected from anhydrous tetrahydro furan, and absolute ether is anhydrous
Methyl tertiary butyl ether(MTBE), anhydrous methylene chloride, dry toluene, anhydrous acetonitrile, anhydrous tertbutyl ether, water and anhydrous 2- methyl tetrahydrochysene furan
One or several kinds in muttering；Reaction temperature is 20~120 DEG C；
Preferably, the compound（5）And compound（6）RMgBr asymmetric 1,2- addition reactions in：Reaction is molten
Agent is selected from anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, the anhydrous tert-butyl group
One or more in ether, anhydrous 2- methyltetrahydrofurans；Reaction temperature is -20~30 DEG C；
It is used as further preferred, compound in reaction（5）And compound（6）RMgBr mol ratio be 1:（1~2.0）；
The structure of chiral ligand is：, chiral ligand and CuBr-SMe2Mol ratio be（2~3）:1.
Preferably, the compound（7）Deprotection-condensation reaction in：Reaction dissolvent is selected from anhydrous methylene chloride, nothing
One or several kinds in water methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans；
Reaction temperature is 20~80 DEG C；Catalyst used in reaction is selected from p-methyl benzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and hydrogen chloride
In one or several kinds.
Beneficial effect：Many relative to the smooth intermediate synthesis step of prior art middle roller, synthesis technique is complicated, present invention synthesis
Method is simple and easy to apply, and cost is relatively low, and yield is higher, and product quality preferably, is adapted to big industrialized production.
Embodiment
The present invention is further described with reference to embodiment.
The method of the smooth intermediate HPLC of roller of the present invention detection purity：
Test apparatus：The high performance liquid chromatographs of Agilent 1100（DAD detectors）.
Chromatographic condition：With OB-H (4.6 × 250mm, 5 μm) for chromatographic column, flow velocity：0.5ml/min.
Mobile phase A：Isopropanol；Mobile phase B：Normal heptane
According to the form below carries out linear gradient elution：
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 1 | 99 |
| 30 | 5 | 95 |
| 50 | 25 | 75 |
| 60 | 45 | 55 |
Ultraviolet detection wavelength：254nm.
The present invention is further described with reference to embodiment.
Embodiment
Compound（4）Preparation
Under nitrogen protection, under the conditions of 0 DEG C, compound is added in 50L reactors（2）1.67 kg（10 mol）In 10L without
In water tetrahydrofuran, the g of copper chloride 67 is added（0.5 mol）, it is slowly added to compound（3）10.5 L（1M tetrahydrofuran solutions）,
After the completion of TLC monitoring reactions, reaction solution ammonium chloride saturated solution（20L）It is 7.0 or so to be neutralized to pH, point liquid, aqueous phase second
Acetoacetic ester is extracted（2 * 10L）, merge organic phase, be concentrated under reduced pressure to obtain compound（4）Crude product, it is anti-that the crude product is directly used in lower step
Should.
Compound（5）Preparation
At ambient temperature, by above-claimed cpd（4）Crude product（10 mol）Add in 50L reactors, add 20L toluene, plus
Enter the kg of benzylamine 1.18（11 mol）, temperature rising reflux, after the completion of TLC monitoring reactions, be concentrated under reduced pressure to obtain compound（5）Crude product, this is thick
Product obtain compound through recrystallization from ethyl acetate/petroleum ether（5）The kg of highly finished product 2.88（8.91 mol）, yield is 89.1%（2 steps）.
HPLC detects purity：98.3%.
1H NMR (400 MHz, CDCl3) δ 7.63 – 7.10 (m, 10H), 4.81 (s, 2H), 4.66 –
4.44 (m, 1H), 4.07 – 3.84 (m, 4H), 3.80 – 3.49 (m, 2H), 2.10 (d, J = 0.5 Hz,
2H), 1.88 – 1.71 (m, 2H), 1.72 – 1.34 (m, 2H).
ESI+ [M+H]+=324.
Compound（7）Preparation
Under nitrogen protection, under the conditions of 0 DEG C, compound is added in 50L reactors（6）3.09 kg（8.8 mol）In 10L
In anhydrous tetrahydro furan, isopropylmagnesium chloride 9L is slowly added to（1M tetrahydrofuran solutions）, compound is made after stirring 3 hours
（6）Obtain RMgBr.
Under nitrogen protection, under the conditions of -20 DEG C, compound is added in 50L reactors（5）2.58 kg（8.0
mol）, catalyst CuBr-SMe2 17 g（0.08 mol）With the g of ligand 1 25（0.16mol）In 10L anhydrous tetrahydro furans, delay
It is slow to add above-claimed cpd（6）RMgBr, TLC monitoring reaction after the completion of, reaction solution ammonium chloride saturated solution（15L）In
Be 7.0 or so to pH, point liquid, aqueous phase is extracted with ethyl acetate（2 * 10L）, merge organic phase, be concentrated under reduced pressure to obtain compound
（7）Crude product, crude product obtains compound through re-crystallizing in ethyl acetate（7）4.23 kg（7.1 mol）, yield is 88.8%.HPLC is detected
Purity：99.1%.
1H NMR (400 MHz, CDCl3) δ 7.85 – 7.74 (s, 1H), 7.74 – 7.60 (s, 2H),
7.54 – 7.13 (m, 10H), 4.84 – 4.66 (m, 1H), 4.64 – 4.42 (m, 2H), 4.06 – 3.78
(m, 3H), 3.78 – 3.36 (m, 4H), 2.33 – 2.12 (m, 1H), 2.02 – 1.84 (m, 1H), 1.83
– 1.68 (m, 1H), 1.66 – 1.53 (m, 3H), 1.52 (s, 1H), 1.45 (d, J = 5.7 Hz, 3H),
1.36 – 1.08 (m, 2H).
ESI+ [M+H]+=596.
Compound（1）Preparation
At ambient temperature, compound is added in 50L reactors（7）4.17 kg（7.0 mol）In 20L absolute ethyl alcohols, then
Add the g of p-methyl benzenesulfonic acid 60（0.35 mol）, it is heated to reflux, after the completion of TLC monitoring reactions, 5L solvents being concentrated under reduced pressure or so,
20L water is slowly added to, stirring and crystallizing, filtering, filter cake 10L water washings dry to obtain compound（1）The kg of highly finished product 3.32（6.4
mol）, yield is 91.4%.HPLC detects purity：99.3%.
1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.69 (s, 2H), 7.62– 7.46 (m,
2H), 7.42 – 7.07 (m, 8H), 5.95 (d, J = 10.8 Hz, 1H), 4.85– 4.72 (m, 1H), 4.70
– 4.57 (m, 1H), 4.47 – 4.33 (m, 1H), 4.21 – 4.12 (m, 1H), 4.11 (d, J = 12.3
Hz, 1H), 3.91 (d, J = 12.3 Hz, 1H), 2.23 – 1.76 (m, 4H), 1.58 (d, J = 5.6 Hz,
3H).
ESI+ [M+H]+=520.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to be said using the present invention
Equivalent structure or equivalent flow conversion that bright book content is made, or other related technical fields are directly or indirectly used in,
Similarly it is included within the scope of the present invention.
Claims (6)
1. a kind of formula（1）The synthetic method of the smooth intermediate of compound roller, it is characterised in that by formula（2）And formula（3）Compound
As initiation material, through following series reaction, formula is finally made（1）Compound, i.e., the described smooth intermediate of roller：
。
2. the synthetic method of the smooth intermediate of roller according to claim 1, it is characterised in that the compound（2）With
Compound（3）Compound is made through condensation reaction（4）；Compound（4）Compound is made through imidization（5）；Compound（5）
And compound（6）RMgBr through asymmetric 1,2- addition reactions be made compound（7）；Final compound（7）Through deprotection-
Compound is made in condensation reaction（1）, i.e., the described smooth intermediate of roller.
3. the synthetic method of the smooth intermediate of roller according to claim 2, it is characterised in that the compound（2）With
Compound（3）Reaction in：Reaction dissolvent is selected from anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous dichloro
One or several kinds in methane, dry toluene, anhydrous acetonitrile, anhydrous tertbutyl ether, water and anhydrous 2- methyltetrahydrofurans；Instead
It is -20~30 DEG C to answer temperature；
The compound（2）And compound（3）Mol ratio be 1:1~1.2；Catalyst used is selected from copper chloride in reaction,
One or several kinds in stannous chloride, copper bromide, cuprous bromide, copper bromide dimethyl disulfide and copper cyanider；Compound（2）With urging
The mol ratio of agent is 200:1~20.
4. the synthetic method of the smooth intermediate of roller according to claim 2, it is characterised in that the compound（4）'s
In reaction：Reaction dissolvent is selected from anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, no water beetle
One or several kinds in benzene, anhydrous acetonitrile, anhydrous tertbutyl ether, water and anhydrous 2- methyltetrahydrofurans；Reaction temperature is 20
~120 DEG C.
5. the synthetic method of the smooth intermediate of roller according to claim 2, it is characterised in that the compound（5）With
Compound（6）RMgBr asymmetric 1,2- addition reactions in：Reaction dissolvent be selected from anhydrous tetrahydro furan, absolute ether,
One in anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans
Plant or several；Reaction temperature is -20~30 DEG C；
Compound in reaction（5）And compound（6）RMgBr mol ratio be 1:（1~2.0）；The structure of chiral ligand
For：, chiral ligand and CuBr-SMe2Mol ratio be（2~3）:1.
6. the synthetic method of the smooth intermediate of roller according to claim 2, it is characterised in that the compound（7）'s
In deprotection-condensation reaction：Reaction dissolvent is selected from anhydrous methylene chloride, and absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol is anhydrous
One or several kinds in tetrahydrofuran and anhydrous 2- methyltetrahydrofurans；Reaction temperature is 20~80 DEG C；Used in reaction
Catalyst be selected from p-methyl benzenesulfonic acid, methanesulfonic acid, the one or several kinds in trifluoroacetic acid and hydrogen chloride.
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| CN201710689505.7A CN107311914A (en) | 2017-08-14 | 2017-08-14 | A kind of synthetic method of the smooth intermediate of roller |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998142A (en) * | 2017-12-16 | 2018-05-08 | 侯瑞玲 | A kind of combination of oral medication for treating myocardial ischemia-reperfusion injury |
-
2017
- 2017-08-14 CN CN201710689505.7A patent/CN107311914A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998142A (en) * | 2017-12-16 | 2018-05-08 | 侯瑞玲 | A kind of combination of oral medication for treating myocardial ischemia-reperfusion injury |
| CN107998142B (en) * | 2017-12-16 | 2018-09-04 | 侯瑞玲 | A kind of combination of oral medication for treating myocardial ischemia-reperfusion injury |
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Application publication date: 20171103 |