CN107118162A - The preparation method of the cyclohexyl epoxide pyrimidine hydrochloride of 2,4,5 triamido 6 - Google Patents
The preparation method of the cyclohexyl epoxide pyrimidine hydrochloride of 2,4,5 triamido 6 Download PDFInfo
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- CN107118162A CN107118162A CN201710293049.4A CN201710293049A CN107118162A CN 107118162 A CN107118162 A CN 107118162A CN 201710293049 A CN201710293049 A CN 201710293049A CN 107118162 A CN107118162 A CN 107118162A
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- triamido
- sodium
- cyclohexyl epoxide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of preparation method of the cyclohexyl epoxide pyrimidine hydrochloride of 2,4,5 triamido 6, exchanged with inorganic base containing sodium with cyclohexanol, then with 2, the chlorine pyrimidine of 4 diaminourea 6, which reacts, obtains the cyclohexyl epoxide pyrimidine of 2,4 diaminourea 6；It is directly added into natrium nitrosum, acetic acid and obtains the cyclohexyl epoxide pyrimidine of 2,4 diaminourea, 5 nitroso 6；The cyclohexyl epoxide pyrimidine of 2,4,5 triamido 6 is obtained with organic solvent, palladium carbon hydrogenating reduction nitroso, ethyl acetate is subsequently added into and/or hydrogen chloride solution obtains the cyclohexyl epoxide pyrimidine hydrochloride of 2,4,5 triamido 6.This method mild condition, prepares and links up, and each step intermediate and product direct plunge into next step without processing, simple to operate, yield height, and raw material are cheap and easy to get, are adapted to amplification and produce.
Description
Technical field
The present invention relates to the preparation method of 2,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, belong to and organise
Product are synthesized and preparing technical field.
Background technology
2,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides are that a kind of synthesizing optical active bio is talked endlessly in one of cry of certain animals
Mesosome, but this kind of optically active biology of nature presence is talked endlessly, cry of certain animals is the formation by chiral selectivity α pteridine rings, and
The cry of certain animals of talking endlessly of this biology can control the symptoms such as Parsons and clinically have the achievement of research.It can both limit the structure for cry of certain animals of talking endlessly
As the multi-functional skeleton in different compound synthesis storehouses being alternatively arranged as, so being widely used in many chiral drugs and bioactivity
The preparation of material.
The content of the invention
It is an object of the invention to provide a kind of preparation method of 2,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides.
The technical proposal of the invention is realized in this way：Step is as follows：
1) with inorganic base containing sodium and cyclohexanol reaction generation hexamethylene sodium alkoxide, then with 2,4 diaminourea -6- chlorine pyrimidines (raw material) are instead
2,4- diaminourea -6- cyclohexyl epoxide pyrimidines should be obtained, the extraction that directly added water after terminating is reacted and goes out；
2) acetic acid, sodium nitrite in aqueous solution are directly added into and carries out nitrosation reaction, reaction end is filtrated to get solid 2,4-
Diaminourea -5- nitroso -6- cyclohexyl epoxide pyrimidines；
3) organic solvent is used, Pd/C 0.1Mpa are hydrogenated with to obtain 2,4,5- triamido -6- cyclohexyl epoxide pyrimidines；
3) it is eventually adding ethyl acetate and/or hydrogen chloride solution obtains 2,4,5- triamido -6- cyclohexyl epoxide pyrimidine salt
Hydrochlorate.Concrete technical scheme is as follows.
Structural formula is as follows：
2,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides
Further, the inorganic base containing sodium is sodium hydride, sodium tert-butoxide, metallic sodium or sodium methoxide.Its consumption is：Hexamethylene
The mass ratio of alcohol, tert-butyl group sodium alkoxide or sodium methoxide is 1：17.5-21.5：1.5-1.7.Cyclohexanol, metallic sodium sodium or sodium hydride
Mass ratio is 1：17.5-21.5：2-2.5.
Further, the organic solvent is methanol, tetrahydrofuran, acetonitrile or ethyl acetate.The organic solvent and original
The mass ratio for expecting (2,4- diaminourea -5- nitroso -6- cyclohexyl epoxides pyrimidine) is 3-15:1.
Further, the Pd/C catalyst is 10%Pd/C or 5%Pd/C.
Beneficial effects of the present invention are：This method mild condition, preparation is coherent, and each step intermediate and product need not handle straight
Input next step is connect, simple to operate, yield is high, and raw material are cheap and easy to get, be adapted to amplification production.
Embodiment
The present invention is further detailed below by instantiation.
Step 1: the synthesis of 2,4- diaminourea -6- cyclohexyl epoxide pyrimidines
(1) vacuum is pumped into 181kg cyclohexanol in the 500L stainless steel kettles of dried and clean, and tertiary fourth is first put into charging hopper
Sodium alkoxide 15.6kg, is warming up to 135 DEG C of temperature in the kettle, and reaction adds raw material 15kg with charging hopper again in 5 hours, reacted 2-3 hours,
Sample HPLC detection raw materials and be less than 0.5%, reaction is cooled to 80 DEG C after terminating, add 32kg water and carry out quenched dilution, treat next
Step application；
(2) vacuum is pumped into 250kg cyclohexanol in the 500L stainless steel kettles of dried and clean, and gold is put into batches with charging hopper
Belong to sodium 6kg, be warming up to 170 DEG C of temperature in the kettle, reaction adds raw material 15kg with charging hopper again in 5 hours, reacted 2-3 hours, temperature
170-175 DEG C of degree, sampling HPLC detection raw materials are less than 0.5%, and reaction is cooled to 80 DEG C after terminating, add 32kg water and be quenched
Dilution, treats next step application；
(3) vacuum is pumped into 250kg cyclohexanol in the 500L stainless steel kettles of dried and clean, and hydrogen is put into batches with charging hopper
Change sodium 7.4kg, be warming up to 155 DEG C of temperature in the kettle, reaction adds raw material 15kg with charging hopper again in 5 hours, reacted 2-3 hours,
155-160 DEG C of temperature, sampling HPLC detection raw materials are less than 0.5%, and reaction is cooled to 80 DEG C after terminating, add 32kg water and quenched
Go out dilution, treat next step application；
(4) vacuum is pumped into 250kg cyclohexanol in the 500L stainless steel kettles of dried and clean, and first is put into batches with charging hopper
Sodium alkoxide 10kg, is warming up to 130 DEG C of temperature in the kettle, and reaction adds raw material 15kg with charging hopper again in 5 hours, reacted 2-3 hours, temperature
155-135 DEG C of degree, sampling HPLC detection raw materials are less than 0.5%, and reaction is cooled to 80 DEG C after terminating, add 32kg water and be quenched
Dilution, treats next step application；
Step 2: the synthesis of 2,4- diaminourea -5- nitroso -6- cyclohexyl epoxide pyrimidines
(1) 20-30 DEG C of temperature in the kettle is controlled, 32kg acetic acid is added, 20min is stirred, the natrium nitrosum prepared is added dropwise molten
Liquid, temperature control carries out reaction 14 hours at 27-32 DEG C.HPLC detection raw materials are less than 3%, after reaction terminates, and water is used in centrifugation
5kg is eluted, then is eluted with MTBE 3kg, obtains violet solid wet product about 34Kg；
Step 3: the synthesis of 2,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides
(1) 2,4- diaminourea -5- nitroso -6- cyclohexyl epoxide pyrimidines 34Kg is put into the white steel reactors of 1000L, plus
Enter ethyl acetate 700kg, 10% wet Pd/C 2Kg.20min is stirred, nitrogen displacement 3 times, hydrogen is replaced 3 times, and 0.1MPa pressurizes are anti-
Answer 16 hours, HPLC detection raw materials are less than 0.1%, after question response is complete, and filtering, filtrate is transferred in 1500L enamel stills, is added dropwise
4 mole of acetic acid ethyl ester hydrogen chloride solutions, adjust PH=2-3, and filtering, filter cake is eluted with ethyl acetate, wet product drying, HPLC detections
Purity is more than 99%, obtains 18Kg products, and HNMR detections are qualified.
(2) 2,4- diaminourea -5- nitroso -6- cyclohexyl epoxide pyrimidines 34Kg is put into the white steel reactors of 1000L, plus
Enter tetrahydrofuran 300kg, 10% wet Pd/C 2Kg.20min is stirred, nitrogen displacement 3 times, hydrogen is replaced 3 times, and 0.1MPa pressurizes are anti-
Answer 16 hours, HPLC detection raw materials are less than 0.1%, after question response is complete, and filtering, filtrate is transferred in 1500L enamel stills, is added dropwise
4 mole of acetic acid ethyl ester hydrogen chloride solutions, adjust PH=2-3, and filtering, filter cake is eluted with ethyl acetate, wet product drying, HPLC detections
Purity is more than 99%, obtains 18Kg products, and HNMR detections are qualified.
(3) 2,4- diaminourea -5- nitroso -6- cyclohexyl epoxide pyrimidines 34Kg is put into the white steel reactors of 1000L, plus
Enter tetrahydrofuran 300kg, 10% wet Pd/C 2Kg.20min is stirred, nitrogen displacement 3 times, hydrogen is replaced 3 times, and 0.1MPa pressurizes are anti-
Answer 16 hours, HPLC detection raw materials are less than 0.1%, after question response is complete, and filtering, filtrate is transferred in 1500L enamel stills, is added dropwise
4 mole of acetic acid ethyl ester hydrogen chloride solutions, adjust PH=2-3, and filtering, filter cake is eluted with ethyl acetate, wet product drying, HPLC detections
Purity is more than 99%, obtains 18Kg products, and HNMR detections are qualified.
(4) 2,4- diaminourea -5- nitroso -6- cyclohexyl epoxide pyrimidines 34Kg is put into the white steel reactors of 1000L, plus
Enter acetonitrile 700kg, 10% wet Pd/C 2Kg.20min is stirred, nitrogen displacement 3 times, hydrogen is replaced 3 times, 0.1MPa pressurizes reaction 16
Hour, HPLC detection raw materials are less than 0.1%, after question response is complete, and filtering, filtrate is transferred in 1500L enamel stills, is added dropwise 36%
Hydrochloric acid solution, adjusts PH=2-3, and filtering, filter cake is eluted with acetonitrile, wet product drying, and HPLC detection purity is more than 99%, obtains
18Kg products, HNMR detections are qualified.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
Any one skilled in the art in the technical scope of present disclosure, technique according to the invention scheme and its
Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.
Claims (7)
1. one kind 2,4, the preparation method of 5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, it is characterised in that 1）First with containing sodium
Inorganic base and cyclohexanol reaction generation hexamethylene sodium alkoxide, then with 2, the reaction of 4 diaminourea -6- chlorine pyrimidines obtains 2,4- diaminourea -6- rings
Base epoxide pyrimidine；2）It is directly added into acetic acid, sodium nitrite in aqueous solution and obtains 2,4- diaminourea -5- nitroso -6- cyclohexyl oxygen
Yl pyrimidines；3）With organic solvent, Pd/C is hydrogenated with to obtain 2,4,5- triamido -6- cyclohexyl epoxide pyrimidines；4）It is eventually adding acetic acid second
Ester and/or hydrogen chloride solution obtain 2,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides.
2. the preparation method of according to claim 12,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, its feature
It is, the inorganic base containing sodium is sodium hydride, sodium tert-butoxide, metallic sodium or sodium methoxide.
3. the preparation method of according to claim 12,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, its feature
It is, the organic solvent is methanol, tetrahydrofuran, acetonitrile or ethyl acetate.
4. the preparation method of according to claim 22,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, its feature
It is, cyclohexanol, the mass ratio of tert-butyl group sodium alkoxide or sodium methoxide is 1： 17.5-21.5 ：1.5-1.7.
5. the preparation method of according to claim 22,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, its feature
It is, cyclohexanol, the mass ratio of metallic sodium sodium or sodium hydride is 1： 17.5-21.5 ：2-2.5.
6. the preparation method of 2 according to claim 1 or 3,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, institute
The mass ratio for stating organic solvent and raw material is 3-15:1.
7. the preparation method of according to claim 12,4,5- triamido -6- cyclohexyl epoxide pyrimidine hydrochlorides, its feature
It is, the Pd/C catalyst is 10% Pd/C or 5%Pd/C.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999050251A2 (en) * | 1998-03-28 | 1999-10-07 | Cancer Research Campaign Technology Limited | Cyclin dependent kinase inhibitors |
| US20150209257A1 (en) * | 2012-10-10 | 2015-07-30 | Henkel Ag & Co. Kgaa | Hair dye agent comprising aminopyrimidine derivatives |
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2017
- 2017-04-28 CN CN201710293049.4A patent/CN107118162A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999050251A2 (en) * | 1998-03-28 | 1999-10-07 | Cancer Research Campaign Technology Limited | Cyclin dependent kinase inhibitors |
| US20150209257A1 (en) * | 2012-10-10 | 2015-07-30 | Henkel Ag & Co. Kgaa | Hair dye agent comprising aminopyrimidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| STEVEN DE JONGHE等: "Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20170901 |