CN106810485A - A kind of Preparation Method And Their Intermediate of chiral boxidine alkanone - Google Patents
A kind of Preparation Method And Their Intermediate of chiral boxidine alkanone Download PDFInfo
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- CN106810485A CN106810485A CN201510846841.9A CN201510846841A CN106810485A CN 106810485 A CN106810485 A CN 106810485A CN 201510846841 A CN201510846841 A CN 201510846841A CN 106810485 A CN106810485 A CN 106810485A
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- boxidine
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- alkanone
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- KTZGCNHMMGZTFN-UYCDIGJJSA-N C[C@H](CC(C1)(C1c(cc1)ccc1-c1ccccc1)N1)C1=O Chemical compound C[C@H](CC(C1)(C1c(cc1)ccc1-c1ccccc1)N1)C1=O KTZGCNHMMGZTFN-UYCDIGJJSA-N 0.000 description 1
- 0 O=*1N[C@](CCc(cc2)ccc2-c2ccccc2)CC1 Chemical compound O=*1N[C@](CCc(cc2)ccc2-c2ccccc2)CC1 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to chiral boxidine alkanone preparation method technical field.The chiral boxidine alkanone preparation method that the present invention is provided is compared with the prior art disclosed in patent WO2008083967, it is to avoid the protection group of upper pivaloyl group, two steps of protection group of Tudor valeryl, route is short；And it is required for serious pollution pivaloyl chloride.The important intermediate compound chirality boxidine alkanone purity for obtaining simultaneously is high, is conducive to the carrying out of subsequent reactions.Present invention also offers multiple new midbody compounds.
Description
Technical field
The invention belongs to the preparation method technical field of chiral boxidine alkanone.
Background technology
There is the preparation method of open chirality boxidine alkanone in patent WO2008083967, pivaloyl chloride is used in middle production procedure, pivalic acid foul smelling, working environment is unfriendly, the pollution to environment is big, and the three wastes are also big.There is accessory substance during the protection group of Tudor valeryl in route disclosed in the patent simultaneously, cannot get purity preferably chirality boxidine alkanone important intermediate 1, while also influenceing yield.
The content of the invention
The purpose of the present invention is that solution above-mentioned technical problem, a kind of new chiral boxidine alkanone preparation method and new intermediate compound are provided, not only purity is high for the chiral boxidine alkanone obtained using the new synthetic method and new intermediate, and whole synthetic route also improves problem of environmental pollution relative to prior art.
It is that, up to above-mentioned purpose, the technical scheme that the present invention takes is as follows：
A kind of preparation method of chiral boxidine alkanone, the method is that the compound 6 of following formula is obtained with palladium carbon catalytic dehydrogenation
Further, above-mentioned hydrogenation is additionally added acidic catalyst, such as sulfuric acid, hydrochloric acid, acetic acid；Preferred 20-50 DEG C of reaction temperature, pressure 5-10kg/cm2。
Further, described compound 6 is reacted with biphenyl RMgBr by the compound 5 of following formula and obtained：
The reactions steps of above-mentioned prepare compound 6, preferably less than -15 DEG C of charge temperature, normal-temperature reaction.
Further, described compound 5 is obtained by the compound 4 of following formula with morpholine condensation reaction:
Condensing agent used by above-mentioned condensation reaction can be selected from DCC (N, N- dicyclohexylcarbodiimides), HOBT (I-hydroxybenzotriazole), DIC (N, N- diisopropylcarbodiimide), one or more of other amino acid condensation agent such as EDC, BDDC, HOAT, BOP, PyBOP, HBTU, TBTU.
Further, described compound 4 is hydrogenated by the compound 3 of following formula and obtained：
Above-mentioned hydrogenation temperature is little on reaction influence, room temperature.Hydrogen is passed through in reaction bulb, can also be reacted under normal pressure, but the reaction time can extend, and preferred pressure limit is normal pressure to 5Kg/cm2.
Further, described compound 3 is that methylation reaction is obtained under alkaline reagent effect by CBZ-L- pyroglutamic acids benzyl ester：
The methylating reagent that described methylation reaction is used is selected from the methylating reagents such as iodomethane, dimethyl suflfate and bromomethane；Described alkaline reagent is selected from the stronger alkaline reagents such as LiHMDS, butyl lithium and double (TMS) potassamides.
Further, described compound 4 can also be obtained by following steps：
1) by Boc-L- pyroglutamic acids benzyl ester, methylation reaction obtains compound 2 under alkaline reagent effect
2) compound 7 is obtained after the compound of formula 2 is acidified, then direct hydrogenation obtains compound 4
Step 1) described in the methylating reagent that uses of methylation reaction be selected from the methylating reagents such as iodomethane, dimethyl suflfate and bromomethane；Described alkaline reagent is selected from the stronger alkaline reagents such as LiHMDS, butyl lithium and double (TMS) potassamides.
Step 2) described in acid be selected from the acid stronger organic acid of the inorganic acid or acetic acid etc. such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid；It is preferred that trifluoroacetic acid, the reaction time is short, and high income, impurity is few.Step 2) it is one pot reaction, obtain after compound 7 without isolating reaction solution, direct hydrogenation.
Beneficial effects of the present invention：
Chiral boxidine alkanone preparation method of the invention is compared with the prior art disclosed in patent WO2008083967, it is to avoid the protection group of upper pivaloyl group, two steps of protection group of Tudor valeryl, route is short；And it is required for serious pollution pivaloyl chloride.The important intermediate compound chirality boxidine alkanone purity for obtaining simultaneously is high, is conducive to the carrying out of subsequent reactions.
Brief description of the drawings
Fig. 1 is the 1H-NMR data of compound 2.
Fig. 2 is the 1H-NMR data of compound 4.
1H-the NMR data of Fig. 3 compounds 7.
Fig. 4 is the 1H-NMR data of compound 5.
Fig. 5 is the 1H-NMR data of compound 6
Fig. 6 schemes for the HPLC of the chiral boxidine alkanone of compound 1 that the inventive method is obtained.
Fig. 7 is the HPLC figures of the chiral boxidine alkanone of compound 1 that patent WO2008083967 methods are obtained.
Specific embodiment
Embodiment 1：The synthesis of compound 2
31.9g (0.1mol) Boc-L- pyroglutamic acid benzyl esters are dissolved in dry tetrahydrofuran, it is cooled to -80 DEG C, the LiHMDS solution of the 1N of 110ml is added dropwise, stirred 30 minutes after dripping off, the iodomethane of 28.4g (0.2mol) is instilled again, and drop finishes, stir about 1 hour, room temperature is warmed naturally to, is stirred overnight.Under ice bath cooling, after adding 200ml saturated ammonium chloride solutions, ethyl acetate to extract, organic layer is washed till neutrality with water, drying is concentrated under reduced pressure into dry.600g silica gel column chromatographies, with ethyl acetate：N-hexane=1：4 wash-outs, obtain intermediate 21.6g.Yield 64.9%, m/z 356.15 (100%, M+Na+ peak), 234.11 (50%, take off Boc peaks).1H—NMR：See accompanying drawing 1.
Embodiment 2：The synthesis of compound 3
The CBZ-L- pyroglutamic acid benzyl esters of 17.7g (0.05mol) are dissolved in dry tetrahydrofuran, it is cooled to -80 DEG C, the LiHMDS solution of the 1N of 75ml is added dropwise, stirred 30 minutes after dripping off, the iodomethane of 14.2g (0.1mol) is instilled again, and drop finishes, stir about 1 hour, room temperature is warmed naturally to, is stirred overnight.Under ice bath cooling, after adding 100ml saturated ammonium chloride solutions, ethyl acetate to extract, organic layer is washed till neutrality with water, drying is concentrated under reduced pressure into dry.Mass spectrum shows m/z 390.16 (M+Na+ peaks).
Embodiment 3：The synthesis of compound 4
The intermediate 2 of 40g (0.12mol) dichloromethane is dissolved, 4.4ml trifluoroacetic acids are added, after being stirred at room temperature 2 hours, decompression removes solvent to dry.Methyl alcohol is added, the Palladium carbon of 1g 10% is hydrogenated in the hydrogenation reaction cauldron of 5Kg/cm2, complete to reacting.Filtering, is concentrated under reduced pressure into dry.The solid 15.8g for obtaining white, yield 92.1%, m/z ES+144.06 (100%M+H+ peaks), 166.03 (M+Na+ peaks) are crystallized with ethyl acetate；ES-142.02 (M-H+ peaks)
Embodiment 4：The synthesis of compound 4
After intermediate 3 is dissolved with methyl alcohol, 10% Palladium carbon is added, hydrogenated in the hydrogenation reaction cauldron of 5Kg/cm2, it is complete to reacting.Filtering, is concentrated under reduced pressure into dry.The solid for obtaining white is crystallized with ethyl acetate, yield is close to 100%.
1H—NMR：See accompanying drawing 2
Embodiment 5：The synthesis of compound 7：
The intermediate 2 of 20g (0.06mol) dichloromethane is dissolved, 2.5ml trifluoroacetic acids are added, after being stirred at room temperature 2 hours, neutrality is washed till with saturated sodium bicarbonate aqueous solution, decompression removes solvent to dry.The solid 12.5g for obtaining white, yield 98.3% are crystallized with n-hexane.
1H-the NMR of compound 7：See Fig. 3
Embodiment 6：The synthesis of intermediate 5
In 1 liter of reaction bulb, add the intermediate 4 of 14.3g (0.1mol), 2gHOBT (I-hydroxybenzotriazole), 12.6g (0.1mol) DIC (N, N- diisopropylcarbodiimides), 8.7g (0.1mol) morpholines and acetonitrile 300ml, are heated to backflow, stirring reaction 2 hours.Cooling, filtering, filtrate decompression is concentrated to dryness, and white solid 20g, yield 93.5%, m/z 213.10 (M+H+ peaks), 235.08 (100%, M+Na+ peaks) are obtained after being crystallized with tetrahydrofuran
1H—NMR：See Fig. 4
Embodiment 7：The synthesis of intermediate 6
The preparation of RMgBr:
Appropriate anhydrous tetrahydro furan, 5.5g (0.23mol) magnesium chips is added to be heated to backflow in four mouthfuls of reaction bulbs of 500ml, 51.3g (0.22mol) is added dropwise to the tetrahydrofuran solution of bromo biphenyl, drips off within 1 hour, continue to flow back 30 minutes, cooling, it is standby.
After 21.2g (0.1mol) intermediate 5 is dissolved with tetrahydrofuran, less than -15 DEG C are cooled to, above-mentioned Grignard solution is added dropwise, drop finishes, and heats up naturally, and reaction is overnight.Hydrochloric acid to the reaction solution that 2N is added dropwise is in faintly acid, and ethyl acetate is extracted, and merges organic layer, is dried, and decompression removes solvent to dry.Off-white powder 24.1g, yield 86.3% are obtained with toluene crystallization.M/z 280.11 (M+H+ peaks), 302.07 (100%, M+Na+ peaks), 581.16 (2M+Na+ peaks)
1H—NMR：See Fig. 5.
Embodiment 8：The synthesis of compound 1
20g raw materials are suspended in tetrahydrofuran, add the palladium carbon of 0.5g sulfuric acid and 2g10%, are hydrogenated 30 hours under 40 DEG C of 55Kg/cm2, are cooled to room temperature, filtering, filter cake is washed with tetrahydrofuran, adds 50ml water, the sodium hydroxide solution of 4g 2M, is heated to 60 DEG C, organic solvent decompression removal.Remaining suspension filtering, filter cake is washed with 50ml, and isopropyl acetate crystallization obtains white solid 15.3g, yield 80.6%.M/z 266.17 (100%, M+H+ peak), 288.15 (100%, M+Na+ peaks).
Product HPLC figures are shown in Fig. 6
Comparative example 9：According to patent WO2008083967 methods prepare compound 1.HPLC figures are shown in Fig. 7.
It can be seen that, the relative chemical purity of the compound 1 obtained with the inventive method is high, reaches 99.77%, substantially without other impurity；The relative chemical purity of compound 1 obtained with existing patent WO2008083967 methods is low, and only 89.95%, the mainly impurity of 15.108min appearances accounts for 9.68%.
HPLC methods：
Post：Aglient C18 150*3mm*3μm
Mobile phase：A- acetonitriles, B-0.09% trifluoroacetic acid aqueous solutions
Flow velocity：1.0ml/min wavelength：254nm temperature：25℃ .
Claims (23)
1. a kind of preparation method of chiral boxidine alkanone, the method is that the compound 6 of following formula is obtained with palladium carbon catalytic dehydrogenation
2. the preparation method of chirality boxidine alkanone as claimed in claim 1, it is characterised in that:Add acidic catalyst sulfuric acid sulphur
Acid, hydrochloric acid or acetic acid.
3. the preparation method of chirality boxidine alkanone as claimed in claim 1, it is characterised in that:20-50 DEG C of reaction temperature, pressure
Power 5-10kg/cm2。
4. the preparation method of chirality boxidine alkanone as claimed in claim 1, it is characterised in that:Described compound 6 passes through
The compound 5 of following formula is obtained with the reaction of biphenyl RMgBr：
5. the preparation method of chirality boxidine alkanone as claimed in claim 4, it is characterised in that:Below -15 DEG C of charge temperature.
6. the preparation method of chirality boxidine alkanone as claimed in claim 4, it is characterised in that:Described compound 5 passes through
The compound 4 of following formula is obtained with morpholine condensation reaction:
7. the preparation method of chirality boxidine alkanone as claimed in claim 6, it is characterised in that:Condensation used by condensation reaction
Agent is selected from one or more of DCC, HOBT, DIC, EDC, BDDC, HOAT, BOP, PyBOP, HBTU and TBTU.
8. the preparation method of chirality boxidine alkanone as claimed in claim 6, it is characterised in that:Described compound 4 passes through
The hydrogenation of compound 3 of following formula is obtained：
9. the preparation method of chirality boxidine alkanone as claimed in claim 8, it is characterised in that:Hydrogenation reaction pressure scope is
Normal pressure is to 5Kg/cm2.
10. the preparation method of chirality boxidine alkanone as claimed in claim 8, it is characterised in that:Described compound 3 be by
CBZ-L- pyroglutamic acids benzyl ester methylation reaction under alkaline reagent effect is obtained：
The preparation method of 11. chirality boxidine alkanones as claimed in claim 10, it is characterised in that:Described methylation reaction makes
Methylating reagent is selected from iodomethane, dimethyl suflfate and bromomethane.
The preparation method of 12. chirality boxidine alkanones as claimed in claim 10, it is characterised in that:Described alkaline reagent choosing
From LiHMDS, butyl lithium and double (TMS) potassamides.
The preparation method of 13. chirality boxidine alkanones as claimed in claim 8, it is characterised in that:Described compound 4 may be used also
Obtained with by following steps：
1) by Boc-L- pyroglutamic acids benzyl ester, methylation reaction obtains compound 2 under alkaline reagent effect
2) compound 7 is obtained after the compound of formula 2 is acidified, then direct hydrogenation obtains compound 4
The preparation method of 14. chirality boxidine alkanones as claimed in claim 13, it is characterised in that:Step 1) described in methylate
The methylating reagent that reaction is used is selected from iodomethane, dimethyl suflfate and bromomethane.
The preparation method of 15. chirality boxidine alkanones as claimed in claim 13, it is characterised in that:Step 1) described in alkali
Property reagent be selected from LiHMDS, butyl lithium and double (TMS) potassamides.
The preparation method of 16. chirality boxidine alkanones as claimed in claim 13, it is characterised in that:Step 2) described in acid choosing
From trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid.
The preparation method of 17. chirality boxidine alkanones as claimed in claim 16, it is characterised in that:Step 2) described in acid be
Trifluoroacetic acid.
18. as following formula compound 2
19. as following formula compound 3
20. as following formula compound 4
21. as following formula compound 5
22. as following formula compound 6
23. as following formula compound 7
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108203396A (en) * | 2016-12-19 | 2018-06-26 | 江西东邦药业有限公司 | A kind of synthesis of enkephalinase inhibitor |
| CN110878039A (en) * | 2019-12-18 | 2020-03-13 | 株洲千金药业股份有限公司 | Preparation method of Sacubitril valsartan sodium impurity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206247A (en) * | 2000-07-21 | 2011-10-05 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
| CN104230865A (en) * | 2013-06-13 | 2014-12-24 | 上海翰森生物医药科技有限公司 | Biaryl-substituted 4-aminobutyric acid derivatives, and preparation method and application thereof |
| WO2015077905A1 (en) * | 2013-11-29 | 2015-06-04 | Merck Sharp & Dohme Corp. | Bicycloamine-substituted-n-benzenesulfonamide compounds with selective activity in voltage-gated sodium channels |
-
2015
- 2015-11-27 CN CN201510846841.9A patent/CN106810485A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206247A (en) * | 2000-07-21 | 2011-10-05 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
| CN104230865A (en) * | 2013-06-13 | 2014-12-24 | 上海翰森生物医药科技有限公司 | Biaryl-substituted 4-aminobutyric acid derivatives, and preparation method and application thereof |
| WO2015077905A1 (en) * | 2013-11-29 | 2015-06-04 | Merck Sharp & Dohme Corp. | Bicycloamine-substituted-n-benzenesulfonamide compounds with selective activity in voltage-gated sodium channels |
Non-Patent Citations (2)
| Title |
|---|
| GHADEER A.R.Y.SUAIFAN ET AL.: "Synthetic approaches to peptides containing the L-Gln-L-Val-D(S)-Dmt motif", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| TARVER, JAMES E. ET AL.: "Hetero-Diels-Alder and pyroglutamate approaches to (2S,4R)-2-methylamino-5-hydroxy-4-methylpentanoic acid", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108203396A (en) * | 2016-12-19 | 2018-06-26 | 江西东邦药业有限公司 | A kind of synthesis of enkephalinase inhibitor |
| CN110878039A (en) * | 2019-12-18 | 2020-03-13 | 株洲千金药业股份有限公司 | Preparation method of Sacubitril valsartan sodium impurity |
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