CN101054331A - Racemization method for asymmetry optical activity 2-heterocycle substituted dihydropyrimidines compound - Google Patents
Racemization method for asymmetry optical activity 2-heterocycle substituted dihydropyrimidines compound Download PDFInfo
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- CN101054331A CN101054331A CN 200710074644 CN200710074644A CN101054331A CN 101054331 A CN101054331 A CN 101054331A CN 200710074644 CN200710074644 CN 200710074644 CN 200710074644 A CN200710074644 A CN 200710074644A CN 101054331 A CN101054331 A CN 101054331A
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- Prior art keywords
- heterocyclic substituted
- optical activity
- compound
- racemization
- dihydropyrimidine compound
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000003287 optical effect Effects 0.000 title claims abstract description 16
- 230000006340 racemization Effects 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 title abstract description 8
- -1 2-substituted dihydropyrimidine compounds Chemical class 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000012065 filter cake Substances 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000003495 polar organic solvent Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 2
- 206010067171 Regurgitation Diseases 0.000 abstract 1
- 230000006837 decompression Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 5
- 101710132601 Capsid protein Proteins 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000013019 agitation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention disclose a asymmetric heterocycle method of optically active 2-substituted dihydropyrimidine compounds, which comprises the following stages in sequence: (1) dissolving resolved 2-substituted dihydropyrimidine compounds wherein a certain optical antipode as the main body in water-soluble polarity organic solvent under regurgitation condition; (2) mixing it 0.5 to 3h; (3) adding 5 to 30% strong alkali water solution, then generating a good deal of solids; (4) filtrating and decompression drying filter cake, then getting the racemic compound which ratio of left-handed to right-handed is 1:1. The present method has advantages of simple operation, strong practicality and easy of industrialization, which can further enhance the utilization ratio of useful heterocycle substituted dihydropyrimidine and save preparing cost.
Description
Technical field
The present invention relates to a kind of racemization method that contains asymmetric optical activity organic compound, the method for carrying out racemization more specifically to a kind of dihydropyrimidine compound that adopts the right title optical activity of strong alkali aqueous solution 2-heterocyclic substituted.
Background technology
The dihydro-pyrimidin that Novel 2-heterocyclically replaces, it is the derivative compound that German Bayer AG is about to the anti-hepatitis one class HAP kind new medicine 4109 (compound patent No. US006696451) of listing, by inventions such as German professors Goldman of Bayer AG, its domestic and international patent No. is CN99805170 and US6503913B1, its medicine can directly combine with HBcAg, suppressing particulate forms, and act on the HBcAg dimer, have an effect with Histidine, quicken the degraded of HBcAg, thereby reach the purpose of hepatitis B virus resisting, EP103769A2 discloses its relevant drug action.
Discover that what have hepatitis virus resisting activity is the dihydro-pyrimidin that left-handed or dextral Novel 2-heterocyclically replaces, the method that obtains the single chiral compound at present has the synthetic and chiral separation of chirality.It is 50% that the theory of racemic modification splits productive rate, and as the fractionation US024878A1 employing chemicrystallization Split Method of Bay-4109, yield can reach about 40%.Chirality synthetic optical purity is difficult to reach more than 95%, generally will unite chiral separation and use, so in the actual procedure of suitability for industrialized production chiral drug, mainly use method for splitting.
The applicant provides a kind of method for splitting of dihydropyrimidine racemic compound of 2-heterocyclic substituted in number for 200710074180.8 patent application in Chinese patent application, this method may further comprise the steps successively: (1) drops into reactor with the dihydropyrimidine racemic compound of 2-heterocyclic substituted with the dinaphthol phosphoric acid ester resolving agent with single optical activity respectively, successively adds polar solvent and non-polar solvent; (2) stir; (3) filter, mother liquor is concentrated freezing placement; (4) filter, mother liquor is concentrated into dried; (5) add organic solvent, stirring and dissolving; Add 10～30% carbonate solution, separatory, extraction and saturated aqueous common salt are stripped, and evaporate to dryness or crystallization, promptly get product.Method for splitting yield of the present invention is about 20%, and optical purity reaches more than 99%; Method for splitting is stable, yield is high, optical purity is high, easy and simple to handle, practical, be easy to industrialization.Resolution yield is about 20% in this chiral separation method, that is to say that 30% levorotatory compound can't split out, dihydropyrimidine compound through the 2-heterocyclic substituted after the chemistry fractionation also has a big chunk useful component to use, and will increase the cost of this drug manufacture greatly if abandon.
Summary of the invention
About becoming again, the dihydropyrimidine compound that a certain optical antipode accounts for the 2-heterocyclic substituted of main body after the objective of the invention is to single split revolves than the racemoid that is 1: 1, it can be split again, thereby will split total recovery to greatest extent near 50%.
Purpose of the present invention can reach by following measure:
The racemization method of the dihydropyrimidine compound of this 2-heterocyclic substituted may further comprise the steps successively:
(1) will split after a certain optical antipode dihydropyrimidine compound that accounts for the 2-heterocyclic substituted of main body under reflux state, be dissolved in the water-soluble polar organic solvent;
(2) stir 0.5h～3h;
(3) a large amount of solids appear in the strong alkali aqueous solution of adding 5～30%;
(4) filter, the filter cake drying under reduced pressure revolves than the racemoid that is 1: 1 about promptly getting;
The general structure of the dihydro-pyrimidin of described 2-heterocyclic substituted is as follows:
Wherein: R
1Phenyl or thienyl that representative is replaced by fluorine and/or chlorine,
R
2Represent C
1-C
6Alkoxyl group,
R
3～R
5Represent hydrogen or C independently of one another
1-C
3Alkyl,
D represents oxygen or sulphur atom.
Described polar solvent is a kind of solvent or more than one a mixed solvent in acetone, ether, methyl alcohol, ethanol, Virahol, ethylene glycol, acetonitrile, pyridine, acetate, dimethyl sulfoxide (DMSO), dimethyl formamide and the tetra oxygen furyl.
Described highly basic is sodium hydroxide, potassium hydroxide, calcium hydroxide.
The present invention has following advantage compared to existing technology:
This racemization method is simple to operate, and is practical, be easy to industrialization, can further improve the utilization ratio to the dihydro-pyrimidin of useful 2-heterocyclic substituted, saves preparation cost.
Embodiment
The invention will be further described according to specific embodiment below.
Embodiment one
The dihydropyrimidine compound that revolves about 100g than being 30: 70 2-heterocyclic substituted is dissolved in the ethanol under reflux state, reflux half an hour, add 5% aqueous sodium hydroxide solution, agitation and filtration, the filter cake drying under reduced pressure obtains revolving about 55g the racemoid than being 1: 1.
Embodiment two
The dihydropyrimidine compound that revolves about 100g than being 35: 65 2-heterocyclic substituted is dissolved in the acetone under reflux state, refluxed 2 hours, and added 20% potassium hydroxide aqueous solution, agitation and filtration, the filter cake drying under reduced pressure obtains revolving about 68g the racemoid than being 1: 1.
Claims (4)
1, a kind of dihydropyrimidine compound racemization method of asymmetric optical activity 2-heterocyclic substituted is characterized in that: may further comprise the steps successively:
(1) will split after a certain optical antipode dihydropyrimidine compound that accounts for the 2-heterocyclic substituted of main body under reflux state, be dissolved in the water-soluble polar organic solvent;
(2) stir 0.5h～3h;
(3) a large amount of solids appear in the strong alkali aqueous solution of adding 5～30%;
(4) filter, the filter cake drying under reduced pressure revolves than the racemoid that is 1: 1 about promptly getting.
2, the dihydropyrimidine compound of asymmetric optical activity 2-heterocyclic substituted according to claim 1 carries out the method for racemization, it is characterized in that: the general structure of the dihydro-pyrimidin of described 2-heterocyclic substituted is as follows:
Wherein: R
1Phenyl or thienyl that representative is replaced by fluorine and/or chlorine,
R
2Represent C
1-C
6Alkoxyl group,
R
3～R
5Represent hydrogen or C independently of one another
1-C
3Alkyl,
D represents oxygen or sulphur atom.
3, the dihydropyrimidine compound of asymmetric optical activity 2-heterocyclic substituted according to claim 1 carries out the method for racemization, it is characterized in that: described water-soluble polar organic solvent is a kind of solvent of acetone, ether, methyl alcohol, ethanol, Virahol, ethylene glycol, acetonitrile, pyridine, acetate, dimethyl sulfoxide (DMSO), dimethyl formamide and tetrahydrofuran (THF) or more than one mixed solvent.
4, the dihydropyrimidine compound of asymmetric optical activity 2-heterocyclic substituted according to claim 1 carries out the method for racemization, it is characterized in that: described highly basic is sodium hydroxide, potassium hydroxide, calcium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710074644 CN101054331A (en) | 2007-05-29 | 2007-05-29 | Racemization method for asymmetry optical activity 2-heterocycle substituted dihydropyrimidines compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710074644 CN101054331A (en) | 2007-05-29 | 2007-05-29 | Racemization method for asymmetry optical activity 2-heterocycle substituted dihydropyrimidines compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101054331A true CN101054331A (en) | 2007-10-17 |
Family
ID=38794410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710074644 Pending CN101054331A (en) | 2007-05-29 | 2007-05-29 | Racemization method for asymmetry optical activity 2-heterocycle substituted dihydropyrimidines compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101054331A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9573941B2 (en) | 2013-11-27 | 2017-02-21 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
-
2007
- 2007-05-29 CN CN 200710074644 patent/CN101054331A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9573941B2 (en) | 2013-11-27 | 2017-02-21 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
| US9617252B2 (en) | 2013-11-27 | 2017-04-11 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
| US9643962B2 (en) | 2013-11-27 | 2017-05-09 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
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| ASS | Succession or assignment of patent right |
Owner name: DONGYANGGUANG INDUSTRY DEVELOPMENT CO., LTD., SHEN Free format text: FORMER OWNER: DONGYANGGUANG PHARMACEUTICAL CO., LTD., GUANGDONG Effective date: 20100925 |
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| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 523871 TO: 518053 |
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| TA01 | Transfer of patent application right |
Effective date of registration: 20100925 Address after: 518053, E25 building, Oriental Garden, overseas Chinese town, Shenzhen, Nanshan District, Guangdong Applicant after: Dongyangguang Industry Development Co., Ltd., Shenzhen Address before: 523871 Guangdong Province, Dongguan city Changan Town Industrial Zone on the sand Fifth East Sunshine science and Technology Park Applicant before: Dongyangguang Pharmaceutical Co., Ltd., Guangdong |
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Open date: 20071017 |