CN110128324A - A kind of Chiral Synthesis and its intermediate of Aiweimopan intermediate - Google Patents
A kind of Chiral Synthesis and its intermediate of Aiweimopan intermediate Download PDFInfo
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- CN110128324A CN110128324A CN201910532069.1A CN201910532069A CN110128324A CN 110128324 A CN110128324 A CN 110128324A CN 201910532069 A CN201910532069 A CN 201910532069A CN 110128324 A CN110128324 A CN 110128324A
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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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses the Chiral Synthesis of Aiweimopan intermediate, it is characterized in that, starting material is used as by formula compound (2) and compound (3), it is reacted through asymmetric conjugated reaction and compound (4) is made, compound (1) Aiweimopan intermediate is finally made through reduction reaction in compound (4), and reaction equation is as follows:
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of Chiral Synthesis of Aiweimopan intermediate and
Wherein mesosome.
Background technique
Aiweimopan (common name: Alvimopan, trade name Entereg), chemical name are as follows: 2- ([(2S) -2- ([(3R,
4R) -4- (3- hydroxy phenyl) -3,4- lupetidine -1- base] methyl) -3- phenylpropionyl] amino) acetic acid.Aiweimopan
Molecular weight: 424.53；CAS registration number: 156053-89-3；Structural formula is shown in formula 5:
Aiweimopan (Alvimopan) is the high selection of GlaxoSmithKline PLC company (GSK) and A Daoluo (Adolor) research and development
Property peripheral mu type opiate receptor antagonistic, in 2008 by FDA list, be used for treating post-operative ileus (POI).It is general next
Abdominal operation is said, due to using opioid analgesic drug, so that gastrointestinal tract malfunction, shows as anorexia, nausea, flatulence, abdomen
Swollen, defecation reduction and intestinal obstruction etc., POI makes troubles to patient's post-operative recovery, and puts off long length of patient stay.Use choosing
The opiate receptor antagonistic of selecting property can effectively alleviate above-mentioned symptom, and the unique peripheral action mechanism of Aiweimopan makes its tool
There is very high targeting feature, is in the current field uniquely with the drug of good clinical effectiveness.
The preparation method for the Aiweimopan reported both at home and abroad at present is mostly with expensive (3R, 4R) -3,4- dimethyl -
4- (3- hydroxy phenyl) piperidines is that N- alkylated reaction occurs for starting material and methyl acrylate, Benzylation anti-in progress later
It answers, hydrolysis, amidation process, obtains Aiweimopan finally by hydrolysis.Reaction route is as follows:
Foreign language literature Improved Process for Preparation of (3R, 4R) -3- (3,4-Dimethyl-4-
piperidinyl)phenol,A Key Intermediate for the Synthesis of
Alvimopan.Org.Process Res.Dev., the reaction route of 2014,18 (1), pp 163-167, announcement are as follows:
In the synthesis technology of domestic and international existing Aiweimopan, cost of material is higher, and reaction route is long, and use compared with
Multiple metal oxide is not easy to remove as catalyst, the heavy-metal residual of product, but also there are product yield is low and quality
The defect of difference.
Summary of the invention
Goal of the invention: in view of the problems of the existing technology, the present invention provides a kind of chiralitys of Aiweimopan intermediate
Synthetic method, the more cheap raw material of use obtain target product by two-step reaction, greatly shorten reaction step, improve
Overall yield of reaction, reduces costs, and this method has many advantages, such as that synthetic yield is high, good product purity.
The present invention also provides a kind of Aiweimopan midbody compound (1), the Aiweimopan intermediate compound compounds
(1) new raw material is provided for Aiweimopan synthesis.
Technical solution: to achieve the goals above, a kind of chiral synthesis side of Aiweimopan intermediate as described herein
Method, which is characterized in that starting material is used as by formula compound (2) and compound (3), reacts obtainedization through asymmetric conjugated reaction
It closes object (4), compound (1) Aiweimopan intermediate is finally made through reduction reaction in compound (4), and reaction equation is as follows:
Wherein, the molar ratio of the compound (2) and compound (3) is 1:1.1~1:1.5.
Preferably, the reaction dissolvent of the compound (2) and compound (3) by asymmetric conjugated reaction reaction is selected from
Anhydrous tetrahydro furan, anhydrous ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, nothing
One or more of water 2- methyltetrahydrofuran and anhydrous acetonitrile.
Preferably, the reaction temperature of the compound (2) and compound (3) by asymmetric conjugated reaction reaction be-
20 DEG C~25 DEG C, time 6-12h.
Preferably, the catalyst of the compound (2) and compound (3) by asymmetric conjugated reaction reaction is selected from
CuCl、CuCl2、CuBr、CuBr2、CuCN、CuBr-SMe2, CuI, CuTC and CuI2One or more of.
Preferably, the compound (2) and compound (3) pass through the chiral ligand structure of asymmetric conjugated reaction reaction
Are as follows:
The synthetic route of chiral ligand is as follows in the present invention:
Wherein, the molar ratio of the catalyst and compound (2) is 1:20~100.
1H NMR(400MHz,CDCl3),δ:1.06-1.98(m,22H),1.83(m,3H),2.52(m,12H),3.46(m,
1H),3.84(s,5H,Fc-H),4.22-4.37(m,3H,Fc-H),7.13-7.69(m,6H,Ph).ESI+[M+H]+=
651.29。
Wherein, the molar ratio of the catalyst and chiral ligand is 1:1~1:1.2.
Preferably, the reaction dissolvent of the reduction reaction of the compound (4) be selected from anhydrous tetrahydro furan, anhydrous ether,
One in anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofuran
Kind is several.
Preferably, the reaction temperature of the reduction reaction of the compound (4) is 0 DEG C~25 DEG C, time 4-6h.
Aiweimopan midbody compound synthesized by the Chiral Synthesis of Aiweimopan intermediate of the present invention
(1), structural formula are as follows:
In the prior art many techniques be withFor the starting material of Aiweimopan synthesis, price is held high
It is expensive.The present invention, which designs the compound (1) that this route obtains, to replace Cl atom by-OH, to reduce raw material by hydrolysis
Cost, and shorten synthesis step.
The utility model has the advantages that compared with prior art, the present invention has the advantage that the present invention provides a kind of completely new love dimensions
The not Chiral Synthesis of Pan's intermediate, middle Aiweimopan intermediate synthesis material is at high cost compared with the existing technology for this method,
Reaction step is more, and synthesis technology is complicated, has synthetic method simple and easy, and cost is relatively low, and yield is higher, and product quality is preferable,
The advantages that raw material is cheap and easy to get, is suitble to big industrialized production.Synthesized Aiweimopan intermediate is Aiweimopan preparation simultaneously
Provide new intermediate feed.
Specific embodiment
Below with reference to embodiment, the present invention will be further explained.
The method of the detection purity of Aiweimopan intermediate HPLC of the present invention:
Test apparatus: 1100 high performance liquid chromatograph of Agilent (DAD detector).
Chromatographic condition: with OD-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: 248nm.
Embodiment 1
The preparation of compound (4)
Under the conditions of -20 DEG C, compound (2) 1.25kg (10.0mol) is added into 50L reaction kettle in 10L reaction dissolvent
In anhydrous methylene chloride, catalyst CuTC 19g (0.1mol) and chiral ligand 71.5g (0.11mol) is added, finally slowly drips
Add compound (3) (11mol, 1M tetrahydrofuran solution, i.e. 11mol compound (3) are dissolved in tetrahydrofuran, concentration 1mol/L), 2
It is dripped off after hour, TLC monitoring 6~10h of reaction process rises to 0 DEG C or so after reaction, is slowly added to 5L saturated ammonium chloride
Aqueous solution, stirring are warmed to room temperature after 30 minutes, and liquid separation, water phase is extracted with dichloromethane, and is then combined with organic phase, and organic phase is subtracting
(0.2mmHg) is concentrated under the conditions of pressure and obtains compound (4) crude product, crude product obtains highly finished product through recrystallization from ethyl acetate/petroleum ether
2.23kg (9.42mol), molar yield 94.2%, HPLC detection purity: 97.3%.
1H NMR(400MHz,DMSO-d6), δ 7.49-7.06 (m, 5H), 6.53 (s, 1H), 3.37 (m, 2H), 2.99 (q, J
=6.6Hz, 1H), 2.01 (dt, J=13.2,5.8Hz, 1H), 1.79 (dt, J=13.2,5.7Hz, 1H), 1.33 (s, 3H),
1.20 (d, J=6.6Hz, 3H)
ESI+[M+H]+=238.
The preparation of compound (1)
Under the conditions of 0 DEG C, under nitrogen protection, into 20L reaction kettle be added compound (4) 2.13kg (9.0mol) in
In 10L reaction dissolvent anhydrous tetrahydro furan, slowly plus Lithium Aluminium Hydride 152g (4mol), added after 1 hour, TLC monitoring react into
Journey 3-6h is warmed to room temperature after reaction, is slowly added to 5L saturated aqueous ammonium chloride, is stirred 30 minutes, liquid separation, and water phase is used
Methylene chloride extraction is then combined with organic phase, and (0.2mmHg) is concentrated at reduced pressure conditions and obtains compound (1) crude product for organic phase, slightly
Product, which are passed through, obtains highly finished product hydrochloride 2.11kg (8.11mol), molar yield 90.1% at salt with hydrogen chloride, and HPLC detects pure
Degree: 97.7%.
1H NMR(400MHz,DMSO-d6) δ 7.47-7.10 (m, 5H), 3.17 (dt, J=12.5,5.4Hz, 1H), 2.97-
2.79 (m, 2H), 2.62 (dd, J=12.5,8.1Hz, 1H), 2.13 (tq, J=8.2,6.5Hz, 1H), 1.84-1.53 (m,
2H), 1.31 (s, 3H), 1.23 (s, 1H), 0.81 (d, J=6.6Hz, 3H)
ESI+[M+H]+=224.
Comparative example 1
Comparative example uses the identical raw material of embodiment 1 and preparation method, the difference is that, in the synthesis of compound (4)
It is added without chiral ligand, compound (4) its molar yield is 54.5%, HPLC detection purity: 80.2%.
Embodiment 2
According to the synthetic method of embodiment 1, the difference is that: the molar ratio 1:1.2 of compound (2) and compound (3),
Reaction temperature is 0 DEG C, and reaction dissolvent is anhydrous methylene chloride, catalyst CuBr2, the molar ratio of catalyst and compound (2)
For 1:60；The molar ratio of catalyst and chiral ligand is 1:1.2.Its molar yield is that 94.5%, HPLC detects purity:
98.25%.
The reaction dissolvent of the reduction reaction of compound (4) is anhydrous ether, and reaction temperature is 25 DEG C.Its molar yield is
90.3%, HPLC detection purity: 97.5%.
Embodiment 3
According to the synthetic method of embodiment 1, the difference is that: the molar ratio 1:1.5 of compound (2) and compound (3),
Reaction temperature is 25 DEG C, and reaction dissolvent is anhydrous acetonitrile, catalyst CuCl2, catalyst and the molar ratio of compound (2) are 1:
20；The molar ratio of catalyst and chiral ligand is 1:1.Its molar yield is 92.3%, HPLC detection purity: 97.4%.
The reaction dissolvent of the reduction reaction of compound (4) is anhydrous methyl tertbutyl ether, and reaction temperature is 20 DEG C.Its mole
Yield is 90.2%, HPLC detection purity: 98.32%.
Claims (10)
1. a kind of Chiral Synthesis of Aiweimopan intermediate, which is characterized in that made by formula compound (2) and compound (3)
It for starting material, is reacted through asymmetric conjugated reaction and compound (4) is made, chemical combination is finally made through reduction reaction in compound (4)
Object (1) Aiweimopan intermediate, reaction equation are as follows:
2. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound
(2) and the molar ratio of compound (3) is 1:1.1~1:1.5.
3. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound
(2) and reaction dissolvent of the compound (3) by asymmetric conjugated reaction reaction preferably is selected from anhydrous tetrahydro furan, anhydrous ether, nothing
Water methyl tertiary butyl ether(MTBE), anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofuran and anhydrous second
One or more of nitrile.
4. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound
(2) and reaction temperature of the compound (3) by asymmetric conjugated reaction reaction is -20 DEG C~25 DEG C, time 6-10h.
5. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound
(2) and catalyst of the compound (3) by asymmetric conjugated reaction reaction is selected from CuCl, CuCl2、CuBr、CuBr2、CuCN、
CuBr-SMe2, CuI, CuTC and CuI2One or more of.
6. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound
(2) and compound (3) passes through the chiral ligand structure that asymmetric conjugated reaction reacts are as follows:
7. the Chiral Synthesis of Aiweimopan intermediate according to claim 4, which is characterized in that the catalyst with
The molar ratio of compound (2) is 1:20~100.
8. the Chiral Synthesis of Aiweimopan intermediate according to claim 5, which is characterized in that the catalyst with
The molar ratio of chiral ligand is 1:1~1:1.2.
9. the Chiral Synthesis of Aiweimopan intermediate according to claim 4, which is characterized in that the compound
(4) reaction dissolvent of reduction reaction is selected from anhydrous tetrahydro furan, anhydrous ether, anhydrous methyl tertbutyl ether, anhydrous dichloromethane
One or more of alkane, dry toluene, anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofuran, the compound (4) are gone back
The reaction temperature of original reaction is 0 DEG C~25 DEG C, time 3-6h.
10. among Aiweimopan synthesized by a kind of Chiral Synthesis of Aiweimopan intermediate as described in claim 1
Body compound (1), structural formula are as follows:
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009068A2 (en) * | 2008-07-16 | 2010-01-21 | Bristol-Myers Squibb Company | Cyclohexenyl modulators of chemokine receptor activity |
| CN101967118A (en) * | 2010-10-14 | 2011-02-09 | 成都名阳药业有限公司 | Preparation method of alvimopan |
| CN102127005A (en) * | 2011-01-05 | 2011-07-20 | 博瑞生物医药技术(苏州)有限公司 | Intermediate of alvimopan and synthesis method thereof |
| CN102757379A (en) * | 2012-07-17 | 2012-10-31 | 上海皓元生物医药科技有限公司 | Preparation method of alvimopan |
| CN105037248A (en) * | 2015-08-10 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Synthesis method of alvimopan |
| CN105198794A (en) * | 2015-10-14 | 2015-12-30 | 湖南华腾制药有限公司 | Preparation method of alvimopan |
-
2019
- 2019-06-19 CN CN201910532069.1A patent/CN110128324A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009068A2 (en) * | 2008-07-16 | 2010-01-21 | Bristol-Myers Squibb Company | Cyclohexenyl modulators of chemokine receptor activity |
| CN101967118A (en) * | 2010-10-14 | 2011-02-09 | 成都名阳药业有限公司 | Preparation method of alvimopan |
| CN102127005A (en) * | 2011-01-05 | 2011-07-20 | 博瑞生物医药技术(苏州)有限公司 | Intermediate of alvimopan and synthesis method thereof |
| CN102757379A (en) * | 2012-07-17 | 2012-10-31 | 上海皓元生物医药科技有限公司 | Preparation method of alvimopan |
| CN105037248A (en) * | 2015-08-10 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Synthesis method of alvimopan |
| CN105198794A (en) * | 2015-10-14 | 2015-12-30 | 湖南华腾制药有限公司 | Preparation method of alvimopan |
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Application publication date: 20190816 |