CN106008362A - Preparation method of novel pyrimidine derivative - Google Patents
Preparation method of novel pyrimidine derivative Download PDFInfo
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- CN106008362A CN106008362A CN201610349669.0A CN201610349669A CN106008362A CN 106008362 A CN106008362 A CN 106008362A CN 201610349669 A CN201610349669 A CN 201610349669A CN 106008362 A CN106008362 A CN 106008362A
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- 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
- C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention provides a preparation method of a novel pyrimidine derivative. The pyrimidine derivative is [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride. The pyrimidine derivative is a new medical intermediate for new drug research and development and screening. The pyrimidine derivative can be applied to the new drug research and development and screening for treating various chronic diseases such as diabetes and alopecia; a synthesis method of the compound also has the advantages of easiness in operation, high efficiency and low raw material cost; and the synthesis path has the advantages of simple and convenient technology and adaptability to factory enlarged production.
Description
Technical field
The present invention relates to the preparation method of a kind of new pyrimidine heterocyclic compounds, be specifically related to a kind of new pyrimidine compound and preparation method thereof.
Background technology
Pyrimidine is a very important heterocyclic compound of class, is widely used in medicine and pesticide field, and numerous studies show that this compounds has preferable biological activity, has important application at parasite killing, sterilization, weeding, antiviral, the aspect such as anticancer.Due to pyrimidine compound have efficiently, the advantage such as low toxicity, model of action are unique；Therefore its MOLECULE DESIGN, synthesis remain a field the most active in heterocyclic compound research with bioactivity research.
Pyrimidines refers to the 6-membered heterocyclic compound in molecular structure containing two nitrogen-atoms, with pyridazine, pyrazine isomers each other.There is special ultraviolet spectra owing to molecular structure existing conjugated double bond.Soluble in water, its alkalescence is more weak than pyridine, is difficult to electrophilic substitution reaction, only in 5-position, bromination reaction can occur, it is impossible to nitrification and sulfonating reaction occur, but is easier to nucleophilic displacement of fluorine, the derivant of pyrimidine is widely present in nature, such as sulfadiazine, barbital, vitamin B1 etc..In nucleic acid, having 3 kinds of important miazines bases, they are uracil, thymus pyrimidine, cytosine, main containing cytosine and thymus pyrimidine in DNA, main containing cytosine and uracil, possibly together with a small amount of miazines modified base in some nucleic acid in RNA.Many medicines, such as sulfadiazine, trimethoprim, Ismipur all contain pyrimidine ring.
Summary of the invention
The shortcoming of prior art in view of the above, it is an object of the invention to provide the preparation method of a kind of novel poyrimidine derivatives.
For achieving the above object and other relevant purposes, the present invention is by including that the technical scheme recorded as follows realizes:
A kind of preparation method of structural formula compound as shown in formula L, described compound is [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride, and formula L is:
Described method comprises the steps:
1) 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde is added to the water, is dividedly in some parts sodium borohydride reaction and obtains 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol；
2) 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol, triphenylphosphine and phthalimide react acquisition 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine under solvent and inert gas conditions with diethyl azodiformate } methyl-isoindole quinoline-1,3-diketone；
3) 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine } methyl-isoindole quinoline-1,3-diketone and hydrazine hydrate in a solvent and under counterflow condition reaction obtain [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride.
Preferably, above-mentioned steps 1) described in sodium borohydride be dividedly in some parts.
Preferably, above-mentioned steps 1) described in the molar ratio of 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde and sodium borohydride be 1:(0.3～0.5).Preferably, above-mentioned steps 1) at 0～10 DEG C add sodium borohydride.Preferably, above-mentioned steps 1) at 0～5 DEG C add sodium borohydride.
It is highly preferred that step 1) reaction carries out post processing to product after terminating, and post processing includes extracting organic facies, precipitation.It is highly preferred that the solvent used during extraction is dichloromethane.It is highly preferred that above-mentioned precipitation is to use anhydrous sodium sulfate to be dried, and concentrated.
Preferably, above-mentioned steps 2) in reaction temperature be-10～25 DEG C.Preferably, above-mentioned steps 2) in 5 DEG C and following temperature and drip diethyl azodiformate under nitrogen protection.It is highly preferred that after dropping diethyl azodiformate, reaction is carried out at ambient temperature.
Preferably, above-mentioned steps 2) in 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol, triphenylphosphine, the mol ratio of phthalimide and diethyl azodiformate be 1:1.1:1.1:1.1.
Preferably, above-mentioned steps 2) in, reaction also includes the post processing to product after terminating, and post processing includes extracting organic facies, precipitation.It is highly preferred that post-processing step includes concentrating THF, then extract.It is highly preferred that use methyl tertiary butyl ether(MTBE) in Cui Qu.The organic facies that extraction obtains sodium hydroxide solution washs, and the aqueous phase of extraction is extracted with ethyl acetate acquisition organic facies.By the step of organic facies precipitation for be dried with anhydrous sodium sulfate.It is highly preferred that after being dried, concentrate dry, mix silica gel and cross post, PE:EA=4:1 rushes post, obtains product MTBE making beating, dries to obtain 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine } methyl-isoindole quinoline-1,3-diketone.
Preferably, step 3) in, 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine } methyl-isoindole quinoline-1,3-diketone is 1:(2～3 with the mol ratio of hydrazine hydrate).Preferably, step 3) in possibly together with solvent.It is highly preferred that described solvent is ethanol.
Preferably, above-mentioned steps 3) in, reaction also includes post processing after terminating, post processing include rotation steam, with MTBE re-dissolved, filter, use HCl wash to aqueous phase, aqueous phase washs with DCM again, then use sodium hydroxide solution to regulate aqueous phase to pH=11, then use DCM extraction, extract anhydrous sodium sulfate to be dried；The dried HCl that is passed through below 10 DEG C, to becoming salt, filters, and drying is to [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride.
The invention also discloses the preparation method of described 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde, comprise the steps:
1) the bromo-6-of the chloro-5-of 4-(2-(2-fluoro-2-methyl) ethyl-pyrimidin and unifor back flow reaction in chloroform obtains N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] }-4-toluene sulfonyl hydrazide；
2) N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] }-4-toluene sulfonyl hydrazide back flow reaction acquisition bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine in alkaline aqueous solution；
3) the bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine first reacts with isopropylmagnesium chloride, then reacts acquisition 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde with N-formyl-morpholine.
Preferably, step 1) in, (2-(2-fluoro-2-methyl) ethyl-pyrimidin is 1:2 with the molar ratio of unifor to the bromo-6-of the chloro-5-of 4-.Preferably, step 1) in reaction under reflux conditions carry out.Preferably, above-mentioned steps 1) in, reaction carries out post processing to product after terminating, and post processing includes lowering the temperature, filter, wash and drying.
Preferably, step 2) in, N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] }-4-toluene sulfonyl hydrazide is dividedly in some parts in reaction system.Preferably, step 2) in, reaction carries out post processing to product after terminating.Preferably, described post processing includes extraction, is dried, and concentrates and does to obtain crude product, and crude product decompression distillation collects fraction 20Pa 50～60 DEG C.It is highly preferred that use MTBE in Cui Qu.
Preferably, above-mentioned steps 3) in reaction system in possibly together with solvent.It is highly preferred that described solvent is THF.Preferably, above-mentioned steps 3) in, the mol ratio that the bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine, isopropylmagnesium chloride feed intake with N-formyl-morpholine is 1:1.1:2.Nitrogen displacement and temperature for-50 DEG C and following in the case of add isopropylmagnesium chloride.And temperature for-50 DEG C and following in the case of add N-formyl-morpholine.
Above-mentioned steps 3) in reaction terminate after use saturated ammonium chloride cancellation, product is carried out post processing, post processing includes extracting organic facies, washs, is dried, concentrates dry acquisition crude product, and mistake post obtains 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde.Preferably, MTBE is selected in extraction.Preferably, post is crossed for using PE:MTBE=15:1 to rinse.
(preparation method of 2-(2-fluoro-2-methyl) ethyl-pyrimidin, in order to use the bromo-6-of 5-, (2-(2-fluoro-2-methyl) ethyl-4-pyrimidone obtains with phosphorus oxychloride reaction to the invention also discloses the 4-bromo-6-of chloro-5-.
Preferably, the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl-4-pyrimidone and the mass ratio 1:(3～5 that feeds intake of phosphorus oxychloride).Preferably, (2-(2-fluoro-2-methyl) ethyl-4-pyrimidone is dividedly in some parts in reaction system the bromo-6-of 5-.Preferably, above-mentioned reaction is under reflux conditions carried out.Preferably, reaction concentrates dry phosphorus oxychloride after terminating, use frozen water cancellation, extract with MTBE, be dried, and crosses post, pull an oar with PE after concentration, the bromo-6-of the chloro-5-of drying 4-(2-(2-fluoro-2-methyl) ethyl-pyrimidin.Preferably, it is dried employing anhydrous sodium sulfate to be dried.Preferably, use PE directly to rush post when crossing post and obtain product.
The invention also discloses the bromo-6-of 5-(preparation method of 2-(2-fluoro-2-methyl) ethyl-4-pyrimidone, for using the method that comprises the steps to obtain:
1) 2-fluorine isobutyrate reacts generation 4-fluoro-4-methyl-3-oxo-pentanoate in a solvent with methyl acetate and potassium tert-butoxide；
2) 4-fluoro-4-methyl-3-oxo-pentanoate and formamidine acetate react generation [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-2-ketone in a solvent and in the basic conditions；
3) [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-2-ketone generates the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl-4-pyrimidone with bromine generation bromination reaction in a solvent.
Preferably, said method step 1) in, solvent is tetrahydrofuran THF.Preferably, solvent also has methyl acetate.Preferably, step 1) in, 2-fluorine isobutyrate, methyl acetate are 1:1.2:1.3 with the mol ratio of potassium tert-butoxide.Preferably, step 1) in reaction temperature be 50～70 DEG C.For example, 65 DEG C.Preferably, step 1) in carry out post processing after completion of the reaction, the technique of post processing includes concentrating dry THF, adding mixture of ice and water, and regulation pH is 3, extracts, washs, is dried, concentrate to do and i.e. obtain 4-fluoro-4-methyl-3-oxo-pentanoate.Preferably, extraction uses MTBE.
Preferably, said method step 2) in solvent be methanol, it be alkaline for using Feldalat NM regulation pH.Preferably, above-mentioned steps 2) in, 4-fluoro-4-methyl-3-oxo-pentanoate is 1:(1.2～1.5 with the mol ratio of formamidine acetate).Preferably, step 2) in reaction temperature be 50～70 DEG C.For example, 65 DEG C.Preferably, said method step 2) in carry out post processing after completion of the reaction, the technique of post processing includes filtering and obtains filtrate, concentrates, dries to obtain crude product, and after then pulling an oar with MTBE, filtering drying obtains [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-2-ketone.
Preferably, said method step 3) in solvent be acetic acid, regulating reactant liquor pH with sodium acetate is faintly acid.Preferably, step 3) in, [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-2-ketone is 1:1 with the mol ratio of bromine.Preferably, during adding bromine, the temperature controlling reaction system is less than 40 DEG C, and interpolation bromine reacts after terminating and at room temperature carries out.Preferably, reaction uses spherical condensation tube.Preferably, said method step 3) in carry out post processing after completion of the reaction, the technique of post processing includes that acetic acid is fallen in concentration, with acetic acid ethyl dissolution, add water and separate organic facies, aqueous phase is extracted with ethyl acetate, the organic facies washing of extraction acquisition and the dry crude product that obtains, and then concentrates after doing with the MTBE making beating also bromo-6-of drying 5-(2-(2-fluoro-2-methyl) ethyl-4-pyrimidone.
The invention also discloses a kind of midbody compound, described midbody compound is 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol, and the formula J of described compound is:
The invention also discloses the purposes of a kind of midbody compound as described above, for the pharmaceutical intermediate as synthesis [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride.
In the present invention, compound described above has the beneficial effect that the present invention provides the new synthetic method of a kind of medicine intermediate and a kind of midbody compound, used by new drug development screening.With the new drug of structural compounds of the present invention and similar structures compound albumen excited and mould have different inhibitory action, and excite mould inhibition to have the strongest selectivity in different albumen.In treatment chronic disease (WO2015095679) such as: in rheumatoid arthritis, psoriatic new drug development, similar structures compound is modified as new drug fragment and has been used widely.As follows:
New compound may be used in the new drug development screening of the treatment treatment various chronic disease such as diabetes, baldness, the synthetic method of this compound also has simple to operate, efficient, the advantage that cost of material is low, this synthetic route has the advantage that technique is simple and convenient, be suitable for factory's amplification production.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of structure compound as shown in formula E.
Fig. 2 is the synthetic route chart of structure compound as shown in formula F.
Fig. 3 is the synthetic route chart of structure compound as shown in formula G.
Fig. 4 is the synthetic route chart of structure compound as shown in formula H.
Fig. 5 is the synthetic route chart of structure compound shown in formula I.
Fig. 6 is the synthetic route chart of structure compound as shown in formula J.
Fig. 7 is the synthetic route chart of structure compound as shown in formula K.
Fig. 8 is the synthetic route chart of structure compound as shown in formula L.
In Fig. 1～8:
A is 2-fluorine isobutyrate and ethyl acetate；
B is potassium tert-butoxide；
C is 4-fluoro-4-methyl-3-oxo-pentanoate；
D is [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-2-ketone；
E is the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl-4-pyrimidone；
F is the 4-bromo-6-of chloro-5-(2-(2-fluoro-2-methyl) ethyl-pyrimidin；
G is N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] }-4-toluene sulfonyl hydrazide；
H is the bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine；
I is 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde；
J is 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol；
K is 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine } methyl-isoindole quinoline-1,3-diketone；
L is [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride.
Detailed description of the invention
Below by way of specific instantiation, embodiments of the present invention being described, those skilled in the art can be understood other advantages and effect of the present invention easily by the content disclosed by this specification.The present invention can also be carried out by the most different detailed description of the invention or apply, and the every details in this specification can also carry out various modification or change based on different viewpoints and application under the spirit without departing from the present invention.
Embodiment 1
The synthesis of 4-fluoro-4-methyl-3-oxo-pentanoate:
THF (25L) is joined in the reactor of 50L, start mechanical agitation, add potassium tert-butoxide (10920g, 97.5mol, 1.3eq), then dropping 2-flaoro methyl isobutyrate (9000g, 75mol, 1eq) and methyl acetate (6660g, 90mol, mixture 1.2eq), drips and is warming up to 65 DEG C after finishing, and reaction is overnight.TLC (PE:EA=4:1) shows after completion of the reaction, concentrates THF, remains about 20L, add 20L mixture of ice and water, adjust pH=3 with 6M HCl, then extract (10L × 2) with MTBE, merging organic facies saturated aqueous common salt washed once, anhydrous sodium sulfate is dried.Concentrate and do to obtain 10000g crude product, yield 74.07%.
Embodiment 2
6-(synthesis of 2-(2-fluoro-2-methyl) ethyl-4-pyrimidone:
Methanol (25L) is joined in 50L reactor, starts mechanical agitation, be dividedly in some parts Feldalat NM (3162g, 58.56mol, 1.9eq), have temperature-rise period.It is cooled to less than 40 DEG C, adds formamidine acetate (3852g, 37.04mol, 1.2eq), then dropping compound 4-fluoro-4-methyl-3-oxo-pentanoate (5000g, 30.86mol, 1eq).Dripping and be warming up to 65 DEG C after finishing, reaction is overnight.TLC (PE:EA=1:1) display raw material reaction is complete.It is passed through HCl gas to system pH=5. to reaction system, stands overnight after having led to.In bottle, solid filters, filter cake acetone heating washing 3 times, filters, merging filtrate and cleaning mixture, concentrates and dry obtain crude product, filter after then pulling an oar with MTBE, dries and there are product 3300g, yield 68.5%.Ms (M+1=157.10)；1H NMR(300MHz,CDCl3) δ 13.3 (br, 1H), 8.15 (s, 1H), 6.69 (s, 1H), 1.69 (s, 3H), 1.61 (s, 3H). (mother solution can be left and taken and cast step bromination).
Embodiment 3
The bromo-6-of the 5-(synthesis of 2-(2-fluoro-2-methyl) ethyl-4-pyrimidone
20L reaction bulb, prepares 0-100 DEG C of thermometer, mechanical agitation, spherical condensation tube.By compound 6-, (2-(2-fluoro-2-methyl) ethyl-4-pyrimidone (1495g, 9.57mol, 1eq) and sodium acetate (785.3g, 9.57mol, 1.1eq), acetic acid (10L) joins in reaction bulb together.Room temperature dropping bromine (1685,10.53,1eq), dropping process has warming phenomenon, controls temperature and is less than less than 40 DEG C, 1h is stirred at room temperature after adding.TLC (PE:EA=1:1) display raw material reaction is complete.Concentrating 7L acetic acid, add EA (5L), dissolve, the 5L that adds water separates organic facies, and aqueous phase EA extracts (5L × 3), and the organic facies saturated aqueous common salt of merging washed once, and anhydrous sodium sulfate is dried.Concentrate dry rear MTBE making beating, dry to obtain 1538g, yield: 68.02%.Ms (M+1=235,237)；1H NMR(300MHz,CDCl3)δ13.3(br,1H),8.22(s,1H),1.83(s,3H),1.76(s,3H).
Embodiment 4
The bromo-6-of the chloro-5-of 4-(synthesis of 2-(2-fluoro-2-methyl) ethyl-pyrimidin, specifically:
Phosphorus oxychloride (2L) is joined in 3L reaction bulb, start mechanical agitation, be dividedly in some parts the bromo-6-of compound 5-(2-(2-fluoro-2-methyl) ethyl-4-pyrimidone (627g, 2.67mol), it is warming up to backflow after adding, reacts 3h.TLC (PE:EA=2:1) display raw material reaction is complete, concentrates dry phosphorus oxychloride, and the phosphorus oxychloride of frozen water cancellation excess, then with MTBE (1.5L × 2), the organic facies saturated aqueous common salt of merging washed once, and anhydrous sodium sulfate is dried.Concentrating and cross post after doing, PE directly rushes post and obtains product, then pulls an oar with PE, dries to obtain white solid 498g.Yield: 73.67%.Ms (M+1=253,255,257)；1HNMR(300MHz,CDCl3)8.82(s,1H),1.88(s,3H),1.81(s,3H)。
Embodiment 5
N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] } synthesis of-4-toluene sulfonyl hydrazide:
By bromo-for compound 4-chloro-5-6-(2-(2-fluoro-2-methyl) ethyl-pyrimidin (1677g, 6.62mol, 1eq) join in 50L reactor with chloroform (20L), start mechanical agitation, it is subsequently adding unifor (2474g, 13.23mol, 2eq), it is warming up to backflow after adding, reacts 3 days.TLC (PE:EA=10:1) display raw material reaction is complete.Naturally being down to room temperature, filter, filter cake MTBE washes twice, dries, obtains product 2252g, yield: 84.3%.
Embodiment 6
The synthesis of the bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine:
40L water is joined in 50L reactor, mechanical agitation, add sodium carbonate (4.5kg, 42.45mol, 2.9eq), be warming up to backflow.Be dividedly in some parts compound N '-{ 4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] }-4-toluene sulfonyl hydrazide (5.9kg, 14.63mol, 1eq), finish rear back flow reaction 2h.TLC (PE:EA=2:1) display raw material reaction is complete, is cooled to room temperature.Adding MTBE extraction (10L × 2), merge organic facies, saturated aqueous common salt washed once, and anhydrous sodium sulfate is dried.Concentrate dry, obtain crude product 1.6kg.Decompression distillation, 20pa 50-60 DEG C collects fraction, altogether 1498g.Yield 46.7%.Ms (M+1=219,221)；1H NMR(300MHz,CDCl3)δ9.04(s,1H),8.85(s,1H),1.85(s,3H),1.77(s,3H).
Embodiment 7
The synthesis of 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-formaldehyde:
THF adds in 5L reaction bulb, starts mechanical agitation, adds the bromo-4-of compound 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine (600g, 2.74mol, 1eq), and nitrogen is replaced, and is cooled to-50 DEG C.Dropping isopropylmagnesium chloride (2.3L, 4.657mol, 1.7eq), drips and reacts 2h after finishing.TLC (PE:EA=6:1) shows that raw material reaction is complete ,-50 DEG C of droppings N-formyl-morpholine (945g, 8.219mol, 3eq), drips and finishes rear room temperature reaction overnight.GC monitoring reaction disappears to raw material, drips saturated ammonium chloride cancellation, and MTBE extracts (5L × 2).Merging organic facies, saturated aqueous common salt washed once, and anhydrous sodium sulfate is dried.Concentrating the dry crude product that obtains, cross post, PE:MTBE=15:1 rushes product.Obtain 350g.Yield 76%.Ms (M+1=169.10)；1H NMR(300MHz,CDCl3)δ10.65(s,1H),9.22(s,1H),9.10(s,1H),1.85(s,3H),1.77(s,3H)。
Embodiment 8
The synthesis of 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol:
2L reaction bulb adds 1.5L water, mechanical agitation, is subsequently adding compound 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-formaldehyde (180g, 1.07mol, 1eq), is cooled to 0-5 DEG C.It is dividedly in some parts sodium borohydride (12.2g, 0.32mol, 0.3eq).TLC (PE:EA=2:1) display raw material reaction is complete, and DCM (500ml × 5) extracts, and merges extraction phase anhydrous sodium sulfate and is dried.Concentrate and do to obtain crude product 149g, yield 83%.
Embodiment 9
2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine } synthesis of methyl-isoindole quinoline-1,3-diketone:
20L reaction bulb, mechanical agitation, add THF (12L); it is subsequently adding compound 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol (1100g, 6.47mol, 1eq); triphenyl phosphorus (1865g, 7.12mol, 1.1eq); phthalimide (1046g, 7.12mol, 1.1eq); it is cooled to 5 DEG C again, under nitrogen protection, drips DEAD (1238g, 7.12mol; 1.1eq), complete rear room temperature reaction is dripped overnight.TLC (PE:EA=2:1) display raw material reaction is complete, concentrates THF, surplus about 5L volume, 5L water is added in residue, MTBE extracts (5L × 2), and the organic facies 1N sodium hydroxide solution of merging washed once, and aqueous phase extracts (2L × 2) with EA again.Merge all of organic facies anhydrous sodium sulfate to be dried.Concentrating dry, mix silica gel and cross post, PE:EA=4:1 rushes post, obtains product MTBE making beating, dries to obtain sterling 723g.Yield: 37%.
Embodiment 10
The synthesis of [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride:
50L reactor, add ethanol (15L), mechanical agitation, add compound 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine methyl-isoindole quinoline-1,3-diketone (1173g, 3.923mol, 1eq), hydrazine hydrate (490g, 9.8mol, 2.5eq), being warming up to backflow, reaction is overnight.TLC (DCM:MeOH=10:1) display raw material reaction is complete, it is cooled to room temperature, dissolve with MTBE after reactant liquor is spin-dried for, filtering, filter cake MTBE washes twice, and product is washed to aqueous phase by the organic facies of merging 2M HCl (2L), aqueous phase washes twice with DCM again, then adjusting pH=11, DCM to extract (2L × 5) aqueous phase with 15% sodium hydroxide solution, combining extraction liquid anhydrous sodium sulfate is dried.Being concentrated into solvent residue 5L, be transferred in 10L reaction bulb, be cooled to less than 10 DEG C, logical HCl is to becoming salt complete.Filter, filter cake washing with acetone three times, dry and to obtain off-white color solid 835g, yield: 91% altogether.Ms (M+1=170.10)；1H NMR(300MHz,dmso)δ9.16(s,1H),8.99(s,1H),6.88(br,3H),1.77(s,3H),1.70(s,3H)。
Additive method step can also be there is before and after described combination step in addition, it is to be understood that the one or more method steps mentioned in the present invention do not repel or additive method step can also be inserted, except as otherwise noted between these steps specifically mentioned；Will also be understood that, combination annexation between the one or more equipment/devices mentioned in the present invention is not repelled and can also be there are other equipment/devices before and after described unit equipment/device or can also insert other equipment/devices, except as otherwise noted between these two equipment/devices specifically mentioned.And, except as otherwise noted, the numbering of various method steps is only the convenient tool differentiating various method steps, rather than for limiting the ordering of various method steps or limiting the enforceable scope of the present invention, being altered or modified of its relativeness, in the case of without essence change technology contents, when being also considered as the enforceable category of the present invention.
The principle of above-described embodiment only illustrative present invention and effect thereof, not for limiting the present invention.Above-described embodiment all can be modified under the spirit and the scope of the present invention or change by any person skilled in the art.Therefore, art has all equivalence modification or changes that usually intellectual is completed under without departing from disclosed spirit and technological thought such as, must be contained by the claim of the present invention.
Claims (10)
1. a preparation method for structural formula compound as shown in formula L, described compound is [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-
Methylamine hydrochloride, formula L is:
Described method comprises the steps:
1) 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde is added to the water, is dividedly in some parts sodium borohydride reaction and obtains 4-[2-(2-
Fluoro-2-methyl) ethyl]-5-pyrimidine-methanol；
2) 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-methanol, triphenylphosphine and phthalimide are at solvent and noble gas
Under the conditions of with diethyl azodiformate react acquisition 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine methyl-isoindole
Quinoline-1,3-diketone；
3) 2-{4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine } methyl-isoindole quinoline-1,3-diketone and hydrazine hydrate are in a solvent and backflow
Under the conditions of reaction obtain [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-5-methylamine hydrochloride.
2. as claimed in claim 1 method, it is characterised in that: step 1) described in sodium borohydride be dividedly in some parts.
3. as claimed in claim 1 method, it is characterised in that: above-mentioned steps 2) in reaction temperature be-10～10 DEG C.
4. method as claimed in claim 1, it is characterised in that: the preparation side of described 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde
Method comprises the steps:
1) (2-(2-fluoro-2-methyl) ethyl-pyrimidin and unifor back flow reaction in chloroform obtains the bromo-6-of the chloro-5-of 4-
N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] }-4-toluene sulfonyl hydrazide；
2) N'-{4-[the bromo-6-of 5-(2-(2-fluoro-2-methyl) ethyl) pyrimidine] } the back flow reaction acquisition in alkaline aqueous solution of-4-toluene sulfonyl hydrazide
The bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine；
3) the bromo-4-of 5-[2-(2-fluoro-2-methyl) ethyl] pyrimidine first reacts with isopropylmagnesium chloride, then reacts with N-formyl-morpholine and obtain
Obtain 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidinecarboxaldehyde.
5. method as claimed in claim 4, it is characterised in that: (2-(2-fluoro-2-methyl) ethyl-pyrimidin is for using for the bromo-6-of the chloro-5-of 4-
(2-(2-fluoro-2-methyl) ethyl-4-pyrimidone obtains the bromo-6-of 5-with phosphorus oxychloride reaction.
6. method as claimed in claim 5, it is characterised in that: (2-(2-fluoro-2-methyl) ethyl-4-pyrimidone is the bromo-6-of described 5-
The method comprised the steps is used to obtain:
1) 2-fluorine isobutyrate reacts generation 4-fluoro-4-methyl-3-oxo-pentanoic acid first in a solvent with ethyl acetate and potassium tert-butoxide
Ester；
2) 4-fluoro-4-methyl-3-oxo-pentanoate and formamidine acetate react generation [4-(1-fluorine in a solvent and in the basic conditions
-1-methyl-ethyl)-pyrimidine]-2-ketone；
3) [4-(1-fluoro-1-methyl-ethyl)-pyrimidine]-2-ketone generates the bromo-6-of 5-(2-(the fluoro-2-of 2-with bromine generation bromination reaction in a solvent
Methyl) ethyl-4-pyrimidone.
7. method as claimed in claim 6, it is characterised in that: step 1) in, solvent is oxolane.
8. as claimed in claim 6 method, it is characterised in that: step 2) in solvent be methanol, using Feldalat NM regulation pH is alkali
Property.
9. a midbody compound, it is characterised in that described midbody compound be 4-[2-(2-fluoro-2-methyl) ethyl]-5-pyrimidine-
Methanol, the formula J of described compound is:
10. a purposes for midbody compound as claimed in claim 9, for as synthesis [4-(1-fluoro-1-methyl-ethyl)-phonetic
Pyridine] pharmaceutical intermediate of-5-methylamine hydrochloride.
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| CN108395408A (en) * | 2018-03-23 | 2018-08-14 | 杰达维（上海）医药科技发展有限公司 | A kind of pharmaceutical intermediate and preparation method thereof |
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