CN110167920A - The method for preparing 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) thiophenol compound - Google Patents
The method for preparing 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) thiophenol compound Download PDFInfo
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- CN110167920A CN110167920A CN201880005989.1A CN201880005989A CN110167920A CN 110167920 A CN110167920 A CN 110167920A CN 201880005989 A CN201880005989 A CN 201880005989A CN 110167920 A CN110167920 A CN 110167920A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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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
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Abstract
The present invention relates to a kind of methods for preparing 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) thiophenol compound.Preparation method according to the present invention passes through in synthesis 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) thiophenol compound when control reaction rate and inhibit runaway reaction, so as to providing the safety of stable yield and preparation process.
Description
Technical field
This application claims preferential based on January 6th, 2017 South Korea patent application submitted the 10-2017-0002309th
Entire contents, are incorporated herein by power by quoting.
The present invention relates to a kind of 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1s for preparing and being indicated by following formula I V
(2H)-pyrimidine radicals) thiophenol compound method:
[formula IV]
Wherein, R1、R2And R3As noted in the discussion.
Background technique
5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzenethiol indicated by above-mentioned formula IV
It closes object and its salt is in the organic synthesis of such as drug and Pesticidal products for synthesizing the compound containing thioether (- S-) group
Important intermediate compound.
For example, Korean Patent No. 1103840 (on January 2nd, 2012) is disclosed using the chemical combination indicated by above-mentioned formula IV
Object synthesizes the uracil base compound with flowering structure with activity of weeding as intermediate.
It is synthesized by one pot reaction by above-mentioned in addition, Korean Patent No. 1345394 (on December 18th, 2013) is disclosed
The method for the compound that formula IV indicates.
However, according to last by all raw materials (such as reducing agent, catalyst and precursor) essence needed for reacting
Property be put into reactor and the above-mentioned one pot reaction that carries out, due to the progress of explosive reaction, in fact it could happen that serious safety problem,
And due to the loss of required product, yield be may be decreased.
Therefore, what present inventors have developed a kind of with various industrial applications can be synthesized with stable yield by
The compound that formula IV indicates is without the improved preparation method of any safety problem, so as to complete the present invention.
Summary of the invention
Technical problem
The present invention, which provides, a kind of safely prepares 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 with stable yield
(2H)-pyrimidine radicals) thiophenol compound method.
Technical solution
To achieve the goals above, the present invention, which provides, a kind of prepares 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1s
(2H)-pyrimidine radicals) thiophenol compound method comprising:
The step of preparing the catalyst mixture containing reducing agent, catalyst and reaction dissolvent；
Reduction reaction step, wherein containing compound represented by following formula I by being added dropwise into the catalyst mixture
Solution, be determined as the generation for the compound of reaction product indicated by Formula Il I, and as wherein mesosome by following formula
The generation and disappearance for the compound that II is indicated；And
Hydrochloric acid is added in the solution containing the compound indicated by above-mentioned formula III to form the change indicated by following formula I V
Close the hydrolysis step of object:
Wherein, in Formulas I into IV, R1And R2It is hydrogen, halogen or alkyl with 1 to 4 carbon atoms each independently；R3
It is hydrogen or alkyl with 1 to 4 carbon atoms.
Beneficial effect
Preparation method according to the present invention passes through in synthesis 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H) -
Pyrimidine radicals) thiophenol compound when control reaction rate and inhibit runaway reaction, so as to ensuring the safety of preparation process
With stable yield.
Specific embodiment
Hereinafter, will be described in preparation 5- (3,6- dihydro -2,6- dioxy -4- fluoroforms of embodiment according to the present invention
Base -1 (2H)-pyrimidine radicals) thiophenol compound method.
Before describing, unless there is clearly opposite explanation in the present specification, otherwise the term is only used for referring to specific
Embodiment, it is no intended to the limitation present invention.
Unless phrase has clearly opposite meaning, otherwise singular used herein includes plural form.
As used herein, term " includes " includes special characteristic, region, integer, step, operation, element and/or ingredient,
And other special characteristics, region, integer, step, operation, element, ingredient and/or group are not precluded the presence or addition of.
Meanwhile the result constantly studied as the present inventor, it was confirmed that if for synthesizing by above-mentioned formula IV
The introducing sequence for changing reactant in the series reaction of the compound of expression, then can inhibit to explode immediately after reaction starts
The runaway reaction carried out to property, and it may thereby be ensured that the safety of preparation process and stable yield.
According to embodiment of the present invention, the present invention, which provides, a kind of prepares 5- (3,6- dihydro -2,6- dioxy -4- three
Methyl fluoride -1 (2H)-pyrimidine radicals) thiophenol compound method comprising:
The step of preparing the catalyst mixture containing reducing agent, catalyst and reaction dissolvent；
Reduction reaction step, wherein containing compound represented by following formula I by being added dropwise into the catalyst mixture
Solution, be determined as the generation for the compound of reaction product indicated by Formula Il I, and as wherein mesosome by following formula
The generation and disappearance for the compound that II is indicated；And
Hydrochloric acid is added in the solution containing the compound indicated by above-mentioned formula III to form the change indicated by following formula I V
Close the hydrolysis step of object:
Wherein, in Formulas I into IV, R1And R2It can be hydrogen, halogen or alkyl with 1 to 4 carbon atoms each independently,
It is preferred that fluorine, chlorine, bromine or iodine, more preferable fluorine or chlorine；R3Can be hydrogen or alkyl with 1 to 4 carbon atoms, preferably hydrogen, methyl,
Ethyl or propyl, more preferable methyl or ethyl.
5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzenethiol indicated by above-mentioned formula IV
Important intermediate can be used as in the field for preparing drug, pesticide etc. by organic synthesis by closing object and its salt.
Particularly, formula IV compound has activity of weeding, and can function properly as the activity for the composition cut weeds
Substance or in which mesosome.
In general, formula IV compound can be obtained by a series of synthesis processes, the synthesis process includes: in reducing agent and to urge
It is formed by the reduction reaction of the compound indicated by Formulas I by the III compound indicated in reaction solution in the presence of agent
Step (reduction reaction step)；And the chemical combination indicated by formula IV is formed by the hydrolysis of the compound indicated by formula III
The step of object (hydrolysis step).
However, if passing through all raw materials needed for reacting, such as reducing agent, catalyst in reduction reaction step
It is substantially disposably put into and is reacted with precursor (compound of formula I), then due to runaway reaction, the yield of required product drops
It is low, and more serious safety problem may occur.
It is suitable by the investment for changing reactant in reduction reaction step in the preparation method of embodiment according to the present invention
Sequence can solve the above problem.
Specifically, according to embodiment of the present invention, formula IV compound can be by comprising the steps of
Method obtains: (i) prepares the catalyst mixture comprising reducing agent, catalyst and reaction dissolvent；(ii) and catalyst mixture
It separates, prepares solution containing a compound of formula I, and be added dropwise in catalyst mixture, to carry out reduction reaction；And
(iii) hydrochloric acid is added in the reaction solution of reduction reaction, so that reaction be hydrolyzed.
In the case where above-mentioned runaway reaction, reduction reaction is explosively carried out, and therefore, it is difficult to control required product
With the generating rate of by-product.
On the other hand, in the preparation method of embodiment according to the present invention, step (i) and step (ii) are separately carried out,
Thus may determine that the generation of the formula III compound of the reaction product as step (ii), and the Formula II as wherein mesosome
The generation and disappearance of compound.
That is, control contains while by changing in determining reduction reaction as the concentration of the Formula II compound of intermediate
There is the solution of compound of formula I to the drop rate of catalyst mixture, runaway reaction can be inhibited and ensures the peace of preparation process
Full property and stable yield.
According to embodiment of the present invention, the type of reducing agent contained in catalyst mixture does not limit especially
System.It is preferable, however, that reducing agent can be selected from by lithium aluminium hydride reduction (LiAlH4), red phosphorus (red P), aluminium chloride (AlCl3), chlorination
Tin (IV) (SnCl4), stannic chloride (II) (SnCl2), zinc chloride (ZnCl2) and zinc metal (Zn) composition at least one of group
Compound.
Based on 1 mole of compound of formula I, reducing agent can include with 1 to 10 mole, 1 to 6 mole or 1 to 4 mole of ratio
In catalyst mixture.
In addition, catalyst contained in catalyst mixture can be iodine (I2)。
Based on 1 moles of reducing agent, catalyst can with 0.001 to 1 mole, 0.005 to 1 mole, 0.005 to 0.5 mole,
Or 0.005 to 0.1 mole of ratio is included in catalyst mixture.
In addition, the type of reaction dissolvent contained in catalyst mixture is not particularly limited.It is preferable, however, that reaction
Solvent can be selected from by acetic acid, ethyl alcohol, methanol, tetrahydrofuran, 4- dioxane, N,N-dimethylformamide, diformazan
At least one of the group of base sulfoxide, acetone, methylene chloride and chloroform composition compound.
Meanwhile dividually preparing solution containing a compound of formula I with catalyst mixture.
Solution containing a compound of formula I is the solution prepared as follows: by compound of formula I be added to in catalyst mixture
In the organic solvent of contained reaction dissolvent identical type and make it completely dissolved.
Solution containing a compound of formula I is added drop-wise in catalyst mixture to carry out reduction reaction.At this point, according to conduct
The concentration of the Formula II compound of reaction intermediate changes, and the drop rate of solution containing a compound of formula I can be controlled can
In the range of inhibiting runaway reaction.
Specifically, Formula II and the variation of the concentration of III compound can be conventional by HPLC etc. in reduction reaction step
Method determines, and if Formula II compound is not detected, terminates reduction reaction step.
It may be advantageous that the reduction reaction step is at 80 DEG C or more, 80 DEG C to 200 DEG C in terms of ensuring reaction efficiency
Or 100 DEG C to 150 DEG C of temperature carries out.
For example, reduction reaction step can contain Formulas I being added dropwise to the catalyst mixture for being heated to 100 DEG C to 150 DEG C
It is carried out while the solution of compound.
Then, by being added to hydrochloric acid containing the compound indicated by formula III obtained by reduction reaction step
Reaction step is hydrolyzed in solution, to form the compound indicated by following formula I V.
The method that hydrolysis step can be stirred to react system by addition hydrochloric acid and at 80 to 120 DEG C carries out.
The formula IV compound generated by hydrolysis step can be recycled by crystallization process.In addition, if it is desired, can
To pass through conventional separation and purification process, for example, the washing, fractionation and column chromatography of organic solvent is used to obtain high purity
Close object.
Hereinafter, illustrating preferred embodiment in order to understand the present invention.However, following embodiment is intended to illustrate invention, but
The invention is not limited thereto.
Embodiment 1
By acetic acid (209.1g), red phosphorus (30.8g, 0.993mol) and iodine (I2, 2.5g, 10mmol) and mixing, then adding
Heat and while be maintained at 80 to 90 DEG C, is stirred 0.5 hour.
Dividually with this, prepare compound solution as follows: by following formula I' compound (the chloro- 4- of 2- fluoro- 5- (3,6- dihydros-
3- methyl -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) phenylsulfonylchloride, 209.1g, 0.497mol) it is added to acetic acid
In (627.4g) and make it completely dissolved.
[Formulas I ']
105 DEG C to 115 DEG C at a temperature of, by compound solution to catalyst mixture be added dropwise 4 hours.It is added dropwise to complete
Afterwards, obtained mixture is stirred 2 hours in relevant temperature range.It confirmed to be used as reaction product during reduction reaction
The generation of formula III ' compound, and the generation and disappearance of Formula II ' the compound as wherein mesosome, and if be not detected
Formula II ' compound, then terminate reduction reaction.At this point, determining that the concentration of Formula II ' compound changes and adjust the same of drop rate
When, carry out reduction reaction:
[Formula II ']
1H NMR (400MHz, CDCl3) δ 7.49~7.46 (m, 2H), 7.34~7.31 (m, 2H), 6.28 (s, 2H), 3.52
(s, 6H).
[formula III ']
1H NMR (400MHz, CDCl3) δ 7.49 (d, J=8.8Hz, 1H), 7.44 (d, J=8.8Hz, 1H), 6.36 (s,
1H), 3.56 (s, 3H), 2.45 (s, 3H).
The reaction solution of reduction reaction is cooled to 80 DEG C and (removing remaining red phosphorus) is filtered by Celite pad.?
10%HCl (72.4g, 0.199mol) is added dropwise within the temperature range of 100 to 110 DEG C, is then stirred 2 hours at 105 DEG C to 110 DEG C
While, reaction is hydrolyzed.Reaction mixture is added drop-wise in water, then stirring is so that product is precipitated as solid.It will precipitating
Solid filter out, then dry, to obtain formula IV ' the compound (169.1g, 96%) in pale solid:
[formula IV ']
1H NMR (400MHz, CDCl3) δ 7.36 (d, J=9.1Hz, 1H), 7.29 (d, J=9.1Hz, 1H), 6.38 (s,
1H), 3.88 (s, 1H), 3.58 (s, 3H).
Comparative example 1
By acetic acid (30mL), red phosphorus (2.21g, 71.2mmol) and iodine (I2, 0.181g, 0.712mmol) and it is mixed and stirred for,
Then Formulas I ' compound (15.0g, 35.6mmol) and while being heated to 120 DEG C is added, is heated to reflux 2 hours.
When the reactions start, reaction explosively carries out, and some reaction mixtures and acetic acid vapor etc. are with unexpected
Fever and leak, then terminate reaction.
During the volatile reduction reaction, it is impossible to be determined as Formula II ' the compound of intermediate generation and
It disappears, and finally determines the generation of formula III ' compound.
After reaction solution is cooled to 100 DEG C, it is slowly added to thereto 1N HCl (6mL), and obtained mixture is existed
110 DEG C are stirred 3 hours.
After reactor is cooled to room temperature, by Celite pad filtering reacting solution, then reaction solution is added to the water
And it is extracted with dichloroethanes.
Combining organic layer water and salt water washing.Organic layer is dry with anhydrous magnesium sulfate, it then filters, is depressurizing
Under the conditions of be concentrated.The compound of concentration is solidified and dried with dichloroethanes/hexane, to obtain linen formula IV ' compound
(10.5g, 83%).
Claims (6)
1. a kind of side for preparing 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) thiophenol compound
Method comprising:
The step of preparing the catalyst mixture containing reducing agent, catalyst and reaction dissolvent；
Reduction reaction step, wherein molten containing compound represented by following formula I by being added dropwise into the catalyst mixture
Liquid is determined as the generation for the compound of reaction product indicated by Formula Il I, and as wherein mesosome by Formula Il table
The generation and disappearance of the compound shown；And
Hydrochloric acid is added in the solution containing the compound indicated by formula III to be formed by the water of the following formula I V compound indicated
Solve reaction step:
Wherein, in Formulas I into IV, R1And R2It is hydrogen, halogen or alkyl with 1 to 4 carbon atoms each independently, and
R3It is hydrogen or alkyl with 1 to 4 carbon atoms.
2. preparation 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzene sulphur as described in claim 1
The method of phenolic compounds, wherein the reducing agent is selected from by lithium aluminium hydride reduction (LiAlH4), red phosphorus (red P), aluminium chloride
(AlCl3), stannic chloride (IV) (SnCl4), stannic chloride (II) (SnCl2), zinc chloride (ZnCl2) and zinc metal (Zn) composition group
At least one of compound.
3. preparation 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzene sulphur as described in claim 1
The method of phenolic compounds, wherein the catalyst is iodine (I2)。
4. preparation 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzene sulphur as described in claim 1
The method of phenolic compounds, wherein the reaction dissolvent is selected from by acetic acid, ethyl alcohol, methanol, tetrahydrofuran, 4- dioxa hexamethylene
At least one of the group of alkane, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methylene chloride and chloroform composition compound.
5. preparation 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzene sulphur as described in claim 1
The method of phenolic compounds, wherein the reduction reaction step is carried out in 80 DEG C to 200 DEG C of temperature.
6. preparation 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) benzene sulphur as described in claim 1
The method of phenolic compounds, wherein R1And R2It is fluorine, chlorine, bromine or iodine each independently；And R3It is hydrogen, methyl, ethyl or propyl.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170002309A KR20180081276A (en) | 2017-01-06 | 2017-01-06 | Method for producing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compounds |
| KR10-2017-0002309 | 2017-01-06 | ||
| PCT/KR2018/000126 WO2018128390A1 (en) | 2017-01-06 | 2018-01-03 | Method for producing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110167920A true CN110167920A (en) | 2019-08-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880005989.1A Withdrawn CN110167920A (en) | 2017-01-06 | 2018-01-03 | The method for preparing 5- (3,6- dihydro -2,6- dioxy -4- Trifluoromethyl-1 (2H)-pyrimidine radicals) thiophenol compound |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR20180081276A (en) |
| CN (1) | CN110167920A (en) |
| WO (1) | WO2018128390A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1122244A1 (en) * | 2000-02-04 | 2001-08-08 | Sumitomo Chemical Company, Limited | Uracil compounds and their use |
| WO2003029226A1 (en) * | 2001-09-26 | 2003-04-10 | Basf Aktiengesellschaft | Heterocyclyl substituted phenoxyalkyl-, phenylthioalkyl-, phenylaminoalkyl- and phenylalkyl-sulfamoylcarboxamides |
| CN103539748A (en) * | 2012-07-13 | 2014-01-29 | 东部福阿母韩农株式会社 | Method for preparing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5281571A (en) * | 1990-10-18 | 1994-01-25 | Monsanto Company | Herbicidal benzoxazinone- and benzothiazinone-substituted pyrazoles |
| MY158047A (en) * | 2008-10-02 | 2016-08-30 | Korea Res Inst Chem Tech | Uracil compounds and a herebicide comprising the same |
-
2017
- 2017-01-06 KR KR1020170002309A patent/KR20180081276A/en active Search and Examination
-
2018
- 2018-01-03 WO PCT/KR2018/000126 patent/WO2018128390A1/en active Application Filing
- 2018-01-03 CN CN201880005989.1A patent/CN110167920A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1122244A1 (en) * | 2000-02-04 | 2001-08-08 | Sumitomo Chemical Company, Limited | Uracil compounds and their use |
| WO2003029226A1 (en) * | 2001-09-26 | 2003-04-10 | Basf Aktiengesellschaft | Heterocyclyl substituted phenoxyalkyl-, phenylthioalkyl-, phenylaminoalkyl- and phenylalkyl-sulfamoylcarboxamides |
| CN103539748A (en) * | 2012-07-13 | 2014-01-29 | 东部福阿母韩农株式会社 | Method for preparing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20180081276A (en) | 2018-07-16 |
| WO2018128390A1 (en) | 2018-07-12 |
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