CN106938987A - The preparation method of the chloromethyluracil of 5 chlorine 6 - Google Patents
The preparation method of the chloromethyluracil of 5 chlorine 6 Download PDFInfo
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- CN106938987A CN106938987A CN201710016945.6A CN201710016945A CN106938987A CN 106938987 A CN106938987 A CN 106938987A CN 201710016945 A CN201710016945 A CN 201710016945A CN 106938987 A CN106938987 A CN 106938987A
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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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Abstract
The present invention provides a kind of chloromethyluracil of 5 chlorine 6 and preparation method thereof, using orotic acid as initiation material, by the esterification of 6 carboxylic acids, and the chlorination of 5 hydrogen restores 6 ester groups for methylol, and occurs chlorination displacement reaction, obtains target product.Simple to operate, process stabilizing of the invention, yield is high, and low cost is adapted to industrial production.
Description
Technical field
Field is synthesized the present invention relates to pharmaceutical chemistry, and in particular to a kind of chloro- 6- chloromethyluracils of prodrug 5-
Preparation method.
Background technology
In September, 2015, a kind of new antimetabolic compound drug thing of Japanese roc (Tahoe Oncology) company exploitation
TAS-102 tablets, FDA approval listings.It is it is a kind of by antitumor nucleoside analog trifluorothymidine (Trifluridine,
Trifluridine, abbreviation FID) and thymidine phosphorylase inhibitor for pyrimidine (Tipiracil, for pyrimidine hydrochloride, letter
Claim TPI) compound medicine of composition, the intractable transfer colorectal cancer patients that are no longer responded for chemotherapy and biotherapy control
Treat.
China's colorectal cancer accounts for tumor incidence 9%, wherein K-ras gene mutations can occur for 40% patient, it is prominent to K-ras
Modification patient, using 5-FU therapeutic schemes without benefit, and TAS-102 clinical effectivenesses performance curative effect is with the obvious advantage.TAS-102 is thin
Born of the same parents' toxin FTD and TPI combination compound drug.TPI is to constitute a kind of new antimetabolic compound drug TAS-102 important components.
Different from the fluorouracil antitumor agent clinically commonly used, FTD is that 5 methyl of thymidine are derived by the nucleic acid that trifluoromethyl replaces
Thing, does not act on RNA, mono-phosphorylated using intracellular thymidine kinase, trifluorothymidine phosplate is formed, with thymus gland synzyme
(TS) combine and suppress DNA synthesis.Because conventional fluorouracil antitumor agent can suppress thymus gland synzyme, DNA conjunction is disturbed
Into, suppress the growth of tumour cell, it is clinically low to conventional fluorouracil antitumor agent sensitiveness, just occur chemotherapy and
The intractable transfer colorectal cancer patients that biotherapy is no longer responded.And TIP is the suppression of FTD digestive enzyme thymidine phosphorylases
Agent, can prevent FTD from orally decomposing afterwards, and TS102 is for treating unresectable late recurrent colorectal cancer patients, meaning weight
Greatly.
The chloro- 6- chloromethyluracils of 5-, also known as：Chloro- 6- chloromethyls -2,4 (1H, the 3H)-hybar Xs of 5-, abbreviation CCMU,
CAS：73742-45-7.CCMU is to constitute TPI construction unit fragments, document report CCMU be synthesis TPI it is unique it is key before
Body, directly synthesizes TPI and (replaces pyrimidine hydrochloride：The chloro- 6- of 5- [(2- imino group -1- pyrrolidines) methyl]-uracil hydrochloride).
The preparation method of the open source literatures such as patent WO9630346 report prepares TPI process routes, brief description of the drawings such as Fig. 1 by CCMU
Therefore, meet CCMU of specification requirements and preparation method thereof, be the key for determining TPI product qualities and cost
Sexual factor.
It is related to the relevant report of CCMU preparation methods, there are many open source literatures.Such as Thomas I Kalman, Li Lai etc.
(Nucleosides, Nucleotides＆Nucleic Acids, 2005,24 (5-7)：367-373)；Corelli, Federico
Deng (Farmaco, 2004,59 (12)：987-992), (the Journal of Pharmacy and such as McNally, VirginiaA.
Pharmacology, 2007,59 (4)：537-547), (the European Journal of Medicinal such as Sun, lingyi
Chemistry, 2013,70：400-410), Yano, Shingo etc. (Bioorganic＆Medicinal Chemistry,
2004,12 (13)：3431-3441), Murray, Paul E. etc. (Bioorganic＆Medicinal Chemistry, 2002,
10(3)：525-530), (the Journal of Medicinal Chemistry, 2003,46 (2) such as Cole, Christian：
207-209), (the Collection of Czech.Chem.Communications, 2011 such as Jansa, Petr：76 (9),
1121-1131), and numerous document report CCMU synthetic routes such as patent WO9630346, brief description of the drawings such as Fig. 2.
These document reports CCMU preparation methods are all with 6- methyluracils (compound A0) it is raw material, by aoxidizing,
The steps such as reduction, 6 chlorinations and 5 chloros synthesize CCMU, and its total recovery is only 18%.In course of reaction, compound A2With
A3, extremely low in most of organic solvent solubilities, purifying products process for refining is complicated, and quality stability is poor, and CCMU preparation
Cost can be multiplied (cost up to ten tens of thousands of yuan/kilogram), further influence TPI product qualities and cost.Therefore, this technique
There is the defect of influence final product quality and production cost in route.
Yuan Jinqiao etc. proposes CCMU new synthesis routes, brief description of the drawings such as Fig. 3 in patent CN105906573A applications.
Compared with WO9630346 etc., CN105906573A is with 6- methyluracils A0For raw material, it is intended to by iodo, also
Former, de- iodine obtains compound A3, A3 total recoverys synthesize CCMU up to 33%, then by similar WO9630346 methods, wherein adopting
With expensive iodination reagent KI and Potassiumiodate, select to be used as de- iodine to the organometallic reagent n-BuLi of water sensitive
Reagent, course of reaction needs to complete in the extremely harsh working condition of anhydrous and oxygen-free and extremely low temperature (less than -80 DEG C), although during
Intermediate dissolubility makes moderate progress, and synthetic route has new meaning, but this route has 6 step reactions steps, from improve final product quality and
For the angle for reducing manufacturing cost, there is the inapparent defect of technical advantage in this synthetic route.
Grandson's equality proposes to improve CCMU synthetic routes, brief description of the drawings such as Fig. 4 in patent CN104945384A applications.
This patent route, with 6- methyluracils A0For raw material, walked by oxidation, 5 chloros, reduction and 6 chlorinations
Suddenly, compound A is synthesized1、A’2And A '3, then chlorination synthesizes CCMU.Compared with WO9630346, compound A '2And A '3It is molten
Xie Xing, than corresponding compound A2And A3Dissolubility be greatly improved, CCMU total recoverys improve twice of (37%), into quality
Amount is improved, and production cost is expected to reduction.
From the foregoing, it will be observed that the technology path of the above-mentioned all open source literatures referred to, is all with 6- methyluracils A0For starting
Raw material, which dictates that unavoidably to use selective oxidant selenium dioxide (selenous acid).It is well known that selenium dioxide has
Acute toxicity, toxic articles, to mucocutaneous stimulation like sulfur dioxide, rat suction selenium dioxide steam 150~
600mg/m3Animal is dead immediately, the product according to《Safety management of dangerous chemical products regulations》By public security department's control, raw material is difficult
, and it is expensive.
The content of the invention
Present invention aims at above-mentioned technical problem is solved, there is provided a kind of purity height, the CCMU preparation methods of high income.Adopt
With cheap scale raw material, not using 6- methyluracils as initiation material, it is to avoid use selective oxidant selenium dioxide
The puzzlement brought, the preparation method is simple to operate, is adapted to industrialization, is conducive to the TPI of further synthesis high quality and low cost.
The method of the present invention comprises the following steps：
1) with orotic acid B0(anhydrous or contain the crystallization water) is initiation material in organic solvent A, adds esterifying reagent：Fat
Fat alcohol or carbonic ester, under activator, catalyst, alkaline auxiliary substance effect, react under suitable temperature, prepare
Compound B1；
2) compound B1In organic solvent B, chlorinating agent, catalyst, in passing through chlorination at suitable temperature are added
Obtain compound B2；
3) compound B2In organic solvent C, in using reducing agent at suitable temperature, under catalyst action, by 6
Reduction, obtains 6- methylol compounds B3；
4) compound B3In organic solvent D, at suitable temperature, chlorinating agent is added, by 6- methylol compounds B3In
6 hydroxy chloride displacement reactions obtain CCMU；
Preferential, described organic solvent A is selected from methanol, ethanol, toluene, chlorobenzene, dimethylbenzene, acetonitrile, Isosorbide-5-Nitrae-dioxy six
Ring and DMF, more preferably dichloromethane, methanol.
Preferential, step 1) in esterifying reagent be selected from methanol, ethanol, isopropanol, the tert-butyl alcohol, 2- chloroethanols, carbonic acid two
Methyl esters, diethyl carbonate, described more preferably methanol.
Preferential, step 1) in activator be selected from thionyl chloride, POCl3, phosphorus trichloride, phosphorus pentachloride, chloro-carbonic acid first
Ester, ethyl chloroformate, isopropyl chlorocarbonate, n-amyl chlorocarbonate, isobutylchloroformate, benzyl chloroformate, chloro-carbonic acid is to nitro
Benzyl ester, oxalyl chloride, described more preferably thionyl chloride.
Preferential, step 1) in catalyst have DMF, pyridine, trifluoroacetic acid, pyrovinic acid, to methyl
Benzene sulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acids, more preferably toluene sulfonic acide (PPTS).
Preferential, step 1) neutral and alkali auxiliary substance is selected from pyridine, triethylamine, sodium carbonate, sodium acid carbonate, potassium carbonate, three
Polyphosphate sodium, more preferably pyridine.
Preferential, step 1) described in suitable temperature ranges be 10~100 DEG C, preferred temperature is 40-80 DEG C.
Preferential, described organic solvent B is selected from dichloromethane, dichloroethanes, trichloroethanes, tetrachloroethanes, glacial acetic acid,
Trifluoroacetic acid, more preferably acetonitrile, glacial acetic acid.
Preferential, step 2) described in chlorinating agent be selected from sulfonic acid chloride, N- chlorosuccinimides, silicon tetrachloride, tetrachloro
Change titanium, chlorine, hypochlorous acid, more preferably perchloric acid, sulfonic acid chloride.
Preferential, step 2) in catalyst be selected from aceticanhydride, trifluoromethanesulfanhydride anhydride, TFAA, ferric trichloride, dichloride
Iron, alchlor, more preferably boron trifluoride, aceticanhydride and ferric trichloride.
Preferential, step 2) described in suitable temperature ranges be 10~100 DEG C, preferred temperature is 80-100 DEG C.
Preferential, described organic solvent C is selected from water, methanol, ethanol, trifluoroethanol, glycol monoethyl ether, tetrahydrochysene furan
Mutter, dimethyl sulfoxide (DMSO), DMF, the mixing of acetonitrile, or its mixed solvent, more preferably tetrahydrofuran and methanol
Thing solvent.
Preferential, step 3) described in reducing agent be selected from lithium aluminium hydride, red aluminum (double (2- methoxyethoxies) aluminum hydrides
Sodium), double (diethylamino) sodium aluminum hydrides, sodium borohydride, potassium borohydride, zinc borohydride, lithium borohydride, calcium borohydride is more excellent
Choosing is sodium borohydride.
Preferential, step 3) described in catalyst be selected from iodine, alchlor, trichlorosilane, zinc chloride is more preferably
Be zinc chloride.
Preferential, step 3) described in suitable temperature ranges be -10~50 DEG C, preferred temperature is 0-10 DEG C.
Preferential, described organic solvent D is selected from dichloromethane, dichloroethanes, trichloroethanes, tetrachloroethanes, glacial acetic acid,
Trifluoroacetic acid, more preferably acetonitrile, dichloromethane.
Preferential, step 4) described in chlorinating agent be selected from methanesulfonic acid chlorine, thionyl chloride, N- chlorosuccinimides, four
Silicon chloride, titanium tetrachloride, chlorine, hypochlorous acid, more preferably perchloric acid, thionyl chloride.
Preferential, step 4) described in suitable temperature ranges be 0~80 DEG C, preferred temperature is 20-50 DEG C.
Especially preferential, the preparation method synthetic route is as follows：
The beneficial effects of the present invention are：
The present invention is first esterified obtained compound B using orotic acid as initiation material1, pass through B15- positions chlorination, so
Afterwards by compound B26- positions be reduced to methylol and chlorination obtains target product, the present invention avoids acute using selective oxidant
Drugs selenium dioxide, it is safe and reliable.
Whey acid esters (the compound B prepared by initiation material orotic acid1) and chloro- whey acid esters (the compound B of 5-2) having
There is good solubility in machine solvent, be conducive to carrying out reduction and reaction is replaced in chlorination, high quality compound CCMU can be prepared,
Total recovery is document report total recovery more than (18%) 3 times up to more than 56%, is the patent of Sun Ping et al. applications
More than 1.5 times of total recovery disclosed in CN104945384A.
Sources of initial raw materials is cheap in industrial-scale production, and production cost is low, and process stabilizing is reliable, to preparing
It is high-quality to provide key prodrug for pyrimidine hydrochloride, be conducive to industrialized production.
Brief description of the drawings
Fig. 1：CCMU prepares TPI process routes
Fig. 2：The CCMU synthetic routes such as WO9630346 patents
Fig. 3：CN105906573A patent CCMU new synthesis routes
Fig. 4：CN104945384A patent CCMU synthetic routes
Embodiment
Below with reference to embodiment, the present invention will be described in detail.But the content of invention is not limited to these implementations
Example, all way of example are not intended to limit the present invention.The side that one of ordinary skill in the art is made according to these embodiments
Conversion in method is all contained in protection scope of the present invention.
Step 1) reaction equation：
Embodiment 1：
At room temperature to equipped with mechanical agitation, reflux condenser, thermometer four-hole boiling flask adds 86g (0.55mol) orotic acid
B0(being free of the crystallization water), 500ml thionyl chlorides, 20ml pyridines and 10mlDMF, are warming up to 75-80 DEG C, back flow reaction 20h, cooling
To room temperature, excessive thionyl chloride liquid is collected in concentration, is added 500ml toluene and is heated up 110 DEG C, continues the 5h that flows back, cool to 50
DEG C, 200ml methanol is slowly added dropwise, maintenance reaction temperature is at 50-60 DEG C, completion of dropping, is warming up to backflow in the middle of without acyl chlorides
Body (TLC detections), reaction is finished, and toluene is collected in concentration, adds 600ml recrystallizing methanols, and hot-air seasoning obtains off-white color and consolidated
Body, surveys fusing point：mp：245 DEG C, obtain 91 grams of (0.53mol) whey acid esters (B1), molar yield：96%.
1HNMR (400MHz, DMSO-d6)δH11.45 (1H, s), 11.21 (1H, s), 6.01 (1H, s), 3.81 (3H, s)
Embodiment 2
At room temperature, by 78g (0.5mol) orotic acids B0(contain the crystallization water) and the sulfuric acid of 5ml 98% add 200ml methanol with
In 200ml dimethyl carbonate mixture solution, flow back 30h, is finished with TLC detections until reacting, the solid being concentrated to give, with heat
Water washing, by filtering water, then uses 300ml recrystallizing methanols, hot-air seasoning obtains off-white powder, surveys fusing point：mp：246
DEG C, obtain 83 grams of (0.49mol) whey acid esters (B1), molar yield 98%.
1HNMR (400MHz, DMSO-d6)δH11.45 (1H, s), 11.21 (1H, s), 6.01 (1H, s), 3.81 (3H, s)
Step 2) reaction equation：
Embodiment 3：
By 68g (0.40mol) whey acid esters (B1) add in 500ml acetic acid, and add 25ml aceticanhydrides and catalytic amount trichlorine
Change iron, be heated to 90-95 DEG C, 0.8g (0.80mol) sulfonic acid chloride is added dropwise, charging is finished, and temperature rising reflux is stayed overnight, until orotic acid
The complete chloro of methyl esters (TLC detections) stops reaction, and reaction solution is cooled into 10 DEG C, solid is filtrated to get, successively with acetic acid and
Water wash, heated-air drying obtains yellow solid, surveys fusing point：mp：250 DEG C, obtain the chloro- whey acid esters of 72.0g (0.35mol) 5-
(B2), molar yield 88%.
1HNMR (400MHz, DMSO-d6) δ H11.82 (1H, s), 11.61 (1H, s), 3.82 (3H, s)
Embodiment 4：
By 60g (0.35mol) whey acid esters (B1) be added in 500ml ethanol, and add 60g (0.45mol) N- chloros
Succimide, is heated to 60-65 DEG C, overnight, until the complete chloro of orotic acid methyl esters (TLC detections) stops reacting, will react
Liquid cools to 10 DEG C, is filtrated to get solid, and with ethyl alcohol recrystallization, heated-air drying obtains light yellow solid, surveys fusing point：mp：251
DEG C, obtain the chloro- whey acid esters (B of 40.0g (0.30mol) 5-2), molar yield 85%.
1H NMR (400MHz, DMSO-d6) δ H11.80 (1H, s), 11.60 (1H, s), 3.84 (3H, s)
Step 3) reaction equation：
Embodiment 5：
By the chloro- whey acid esters (B of 49g (0.24mol) 5-2) and 46g (1.2mol) sodium borohydride powder be dispersed in 200ml tetra-
In hydrogen tetrahydrofuran solution, strong stirring is slowly added into 25ml methanol, flows back 14 hours, TLC detection reactions, is cooled to room temperature, adds
300mlNH4The Cl aqueous solution, continues to stir 10h, separates organic layer, aqueous phase is extracted, is associated with three times with 300ml ethyl acetate
Machine phase, is dried and is filtered to remove with magnesium sulfate, obtains light yellow organic phase, is concentrated to dryness, and with ethyl alcohol recrystallization, obtains light yellow
Solid, obtains the chloro- 6- methylols uracil (B of 40g (0.22mol) 5-3), molar yield 90%..
1HNMR (400MHz, DMSO-d6) δ H11.30 (1H, s), 11.40 (1H, s), 4.65 (2H, s)
Embodiment 6：
Under strong stirring, 25g (0.66mol) sodium borohydride powder and 5g (0.04mol) zinc chloride powder are dispersed in
In 150ml tetrahydrofuran solutions, the chloro- whey acid esters (B of 25g (0.12mol) 5- are slowly added into2), flow back 14 hours, be cooled to room
Temperature, adds 20mlNH4The Cl aqueous solution, continues to stir 15h, separates organic layer, aqueous phase is extracted in three times with 200ml ethyl acetate,
Merge organic phase, dried and be filtered to remove with magnesium sulfate, obtain yellow organic phase, be concentrated to dryness, with ethyl alcohol recrystallization, obtain shallow
Yellow solid, surveys fusing point, obtains the chloro- 6- methylols uracil (B of 5-3)。
Step 4) reaction equation：
Embodiment 7：
By the chloro- 6- methylols uracil (B of 60g (0.34mol) 5- at a temperature of 25-30 DEG C3) and 20mlDMF sequentially add
Into 600ml dichloromethane solvents, heating is heated to backflow, 400g thionyl chlorides (steaming again) is slowly added dropwise, charging is finished, and is continued
Backflow is until compound B3Material disappearance terminating reaction, is cooled to room temperature filtering, filter cake eluent methylene chloride, with hot wash,
Filter cake is collected, at a temperature of 50-60 DEG C, hot-air seasoning obtains 56g (0.29mol) yellow solid, and the chloro- 6- chloromethyls urine of 5- is phonetic
Pyridine (CCMU) yield 85%.
IR (KBr) 3161,3042,2844,1702,1694,1428,1287,826,744cm-1
1H NMR(DMSO-d6) δ 4.73 (s, 2H), 11.1 (br, s, 2H)
13C NMR(DMSO-d6) (CH) of δ 163 (c), 151 (C), 150 (C), 100 (CH), 50
MS 194.9(M+H)+。
Claims (21)
1. a kind of chloro- 6- chloromethyluracils (CAS of 5-：73742-45-7, abbreviation CCMU) preparation method, it is characterised in that
Synthetic route is：
Comprise the following steps：
A. it is initiation material in organic solvent A using orotic acid, adds esterifying reagent：Fatty alcohol or carbonic ester, in activator, are urged
Under agent, alkaline auxiliary substance effect, reacted under suitable temperature, prepare compound B1；
B. compound B1In organic solvent B, chlorinating agent, catalyst, in passing through chlorination at suitable temperature are added
Compound B2；
C. compound B2In organic solvent C, in using reducing agent at suitable temperature, under catalyst action, by 6 reduction,
Obtain 6- methylol compounds B3；
D. compound B3In organic solvent D, at suitable temperature, chlorinating agent is added, by 6- methylol compounds B3In 6
Hydroxy chloride displacement reaction obtains the chloro- 6- chloromethyluracils (CCMU) of target product 5-.
2. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described starting
Raw material is orotic acid.
3. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described starting
Raw material orotic acid is containing the crystallization water.
4. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described starting
Raw material orotic acid is free from the crystallization water.
5. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described is organic
Solvent orange 2 A is selected from methanol, ethanol, toluene, chlorobenzene, dimethylbenzene, acetonitrile, Isosorbide-5-Nitrae-dioxane and DMF, dichloro
Methane, more preferably methanol.
6. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that be esterified in step a
Reagent be selected from methanol, ethanol, isopropanol, the tert-butyl alcohol, 2- chloroethanols, dimethyl carbonate, diethyl carbonate, it is described more preferably
Methanol.
7. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that preferential, step
Activator is selected from thionyl chloride, POCl3, phosphorus trichloride, phosphorus pentachloride, methylchloroformate, ethyl chloroformate, chloro-carbonic acid in a
Isopropyl ester, n-amyl chlorocarbonate, isobutylchloroformate, benzyl chloroformate, nitrobenzyl chloroformate ester, oxalyl chloride, it is described more
Preferably thionyl chloride.
8. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that preferential, step
Catalyst has DMF, pyridine, trifluoroacetic acid, pyrovinic acid, p-methyl benzenesulfonic acid, sulfuric acid, hydrochloric acid, phosphorus in a
Acid, polyphosphoric acids, more preferably toluene sulfonic acide (PPTS).
9. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that preferential, step
A neutral and alkalis auxiliary substance is selected from pyridine, triethylamine, sodium carbonate, sodium acid carbonate, potassium carbonate, more preferably sodium tripolyphosphate, pyridine.
10. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that preferential, step
Suitable temperature ranges described in rapid a are 10~100 DEG C, and preferred temperature is 40-80 DEG C.
11. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described is organic
Solvent B is selected from dichloromethane, and dichloroethanes, trichloroethanes, tetrachloroethanes, glacial acetic acid, trifluoroacetic acid, acetonitrile is more preferably
Glacial acetic acid.
12. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step b
The chlorinating agent stated be selected from sulfonic acid chloride, N- chlorosuccinimides, silicon tetrachloride, titanium tetrachloride, chlorine, hypochlorous acid, perchloric acid, more
Preferably sulfonic acid chloride.
13. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that urged in step b
Agent is selected from aceticanhydride, and trifluoromethanesulfanhydride anhydride, TFAA, ferric trichloride, ferrous chloride, alchlor, boron trifluoride is more excellent
Choosing is aceticanhydride and ferric trichloride.
14. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step b
The suitable temperature ranges stated are 10~100 DEG C, and preferred temperature is 80~100 DEG C.
15. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described is organic
Solvent C is selected from water, methanol, ethanol, trifluoroethanol, glycol monoethyl ether, tetrahydrofuran, dimethyl sulfoxide (DMSO), N, N- dimethyl methyls
Acid amides, acetonitrile, or its mixed solvent, more preferably tetrahydrofuran and carbinol mixture solvent.
16. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step c
The reducing agent stated be selected from lithium aluminium hydride, red aluminum (double (2- methoxyethoxies) sodium aluminum hydrides), double (diethylamino) sodium aluminum hydrides,
Sodium borohydride, potassium borohydride, zinc borohydride, lithium borohydride, more preferably calcium borohydride, sodium borohydride.
17. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step c
The catalyst stated is selected from iodine, and alchlor, trichlorosilane, zinc chloride is more preferably zinc chloride.
18. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step c
The suitable temperature ranges stated are -10~50 DEG C, and preferred temperature is 0~10 DEG C.
19. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that described is organic
Solvent D is selected from dichloromethane, and dichloroethanes, trichloroethanes, tetrachloroethanes, glacial acetic acid, trifluoroacetic acid, acetonitrile is more preferably
Dichloromethane.
20. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step d
The chlorinating agent stated is selected from methanesulfonic acid chlorine, thionyl chloride, N- chlorosuccinimides, silicon tetrachloride, titanium tetrachloride, chlorine, secondary chlorine
Acid, more preferably perchloric acid, thionyl chloride.
21. the preparation method of the chloro- 6- chloromethyluracils of 5- according to claim 1, it is characterised in that institute in step d
The suitable temperature ranges stated are 0~80 DEG C, and preferred temperature is 20~50 DEG C.
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| CN201710016945.6A CN106938987A (en) | 2017-01-11 | 2017-01-11 | The preparation method of the chloromethyluracil of 5 chlorine 6 |
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| CN201710016945.6A CN106938987A (en) | 2017-01-11 | 2017-01-11 | The preparation method of the chloromethyluracil of 5 chlorine 6 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107118164A (en) * | 2017-02-08 | 2017-09-01 | 卡硼瑞（北京）科技有限公司 | 5 chlorine 6（Chloromethyl）‑2,4‑（1H,3H）The preparation method of hybar X |
| CN107298656A (en) * | 2017-06-21 | 2017-10-27 | 四川同晟生物医药有限公司 | For pyrimidine intermediate and for pyrimidine intermediate, for pyrimidine, for the preparation method of pyrimidine hydrochloride |
| CN108059617A (en) * | 2018-02-06 | 2018-05-22 | 成都倍特药业有限公司 | The impurity and its synthetic method of the chloro- 6- ethyls -5-FUs of voriconazole starting material 4- |
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| CN101938905A (en) * | 2007-12-24 | 2011-01-05 | 辛根塔有限公司 | Chemical compounds |
| CN104725324A (en) * | 2015-03-23 | 2015-06-24 | 上海皓元生物医药科技有限公司 | Preparation method of 6-chloromethylpyrimidine-2,4-(1H, 3H)-diketone |
| CN104945384A (en) * | 2014-03-25 | 2015-09-30 | 江苏豪森药业股份有限公司 | Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof |
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| CN101938905A (en) * | 2007-12-24 | 2011-01-05 | 辛根塔有限公司 | Chemical compounds |
| CN104945384A (en) * | 2014-03-25 | 2015-09-30 | 江苏豪森药业股份有限公司 | Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof |
| CN104725324A (en) * | 2015-03-23 | 2015-06-24 | 上海皓元生物医药科技有限公司 | Preparation method of 6-chloromethylpyrimidine-2,4-(1H, 3H)-diketone |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107118164A (en) * | 2017-02-08 | 2017-09-01 | 卡硼瑞（北京）科技有限公司 | 5 chlorine 6（Chloromethyl）‑2,4‑（1H,3H）The preparation method of hybar X |
| CN107298656A (en) * | 2017-06-21 | 2017-10-27 | 四川同晟生物医药有限公司 | For pyrimidine intermediate and for pyrimidine intermediate, for pyrimidine, for the preparation method of pyrimidine hydrochloride |
| CN108059617A (en) * | 2018-02-06 | 2018-05-22 | 成都倍特药业有限公司 | The impurity and its synthetic method of the chloro- 6- ethyls -5-FUs of voriconazole starting material 4- |
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