CN110437093A - The preparation method of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of one kind (S) -5- - Google Patents
The preparation method of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of one kind (S) -5- Download PDFInfo
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- CN110437093A CN110437093A CN201910822312.3A CN201910822312A CN110437093A CN 110437093 A CN110437093 A CN 110437093A CN 201910822312 A CN201910822312 A CN 201910822312A CN 110437093 A CN110437093 A CN 110437093A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
Abstract
The preparation method of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of one kind (S) -5-, comprising the following steps: (1) fluorine arene compounds are reacted with organometallic reagent, obtain ortho position metal intermediates；(2) the ortho position metal intermediates that step (1) obtains react with acetylation reagent, obtain the aceted intermediate after post treatment after the reaction was completed.This method reaction route is short, easy to operate, environmental-friendly, safer, economical, is with a wide range of applications.
Description
Technical field
The invention belongs to the preparation methods of pharmaceutical intermediate, more particularly, to used in Lorlatinib (Laura replaces Buddhist nun)
The preparation method of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of important source material (S) -5-.
Background technique
Laura is for one kind novel, reversible, potent the small molecule ALK and ROS1 that Buddhist nun (Lorlatinib) is that Pfizer develops
Inhibitor all has very strong inhibiting effect to medicament-resistant mutation known to ALK, thus is known as the 3rd generation ALK inhibitor.
(S) the fluoro- 3- methyl isobenzofuran -3- ketone of -5- is the primary raw material for producing Lorlatinib (Laura replaces Buddhist nun), is a kind of
Important chemical industry, medicine intermediate, can be used for the multiple fields such as dyestuff, hair dye, medicine, pesticide material.
Preparation method about the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- reports less, existing preparation (S) -5-
Fluoro- 3- methyl isobenzofuran -3- ketone will generally use following aceted intermediate:
DMG:-CON-R、-CONR2、Deng.
But the synthesis report of the intermediate is also less, it is now known that have clearly report be Org.Process
Res.Dev.2017,21,1340-1348, the synthetic method of this article report is, as raw material, carboxyl to be protected to fluorobenzoyl chloride
Shield, which becomes, has strong ortho position homing device (Directed Metalation Group--DMG), then in Grignard Reagent or alkane
Under the effect of base lithium compound, alcohol is first generated with acetaldehyde, is reoxidized as title intermediate.Synthetic method is as follows:
The document also mentions a direct step and the method that acetylation reagent accomplishes ketone is added simultaneously, if acetylation reagent is vinegar
Acid anhydrides and chloroacetic chloride, reaction can obtain complicated mixture；If acetylation reagent is N- methoxy N-methylacetamide, instead
Should result it is good but drop at high cost is not got off, do one step of acetylation reagent so not having to N- methoxy N-methylacetamide and accomplish
Ketone, selection are completed in two steps.
The inventors discovered that used acetaldehyde is easy gasification during the reaction when using above method, can give birth to
It is seriously polluted at a large amount of byproducts, it is not easy industrialized production, and reaction step is long, economic benefit is low.
Summary of the invention
For green and the aceted intermediate of the low cost synthesis fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5-, this hair
It is bright to provide a kind of green synthesis method of aceted intermediate for preparing the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5-.
The preparation method of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of one kind (S) -5-, including following step
It is rapid:
(1) fluorine arene compounds are reacted with organometallic reagent, obtains ortho position metal intermediates；
Shown in structure to the fluorine arene compounds such as formula (I):
(2) the ortho position metal intermediates that step (1) obtains react with acetylation reagent, and warp is located later after the reaction was completed
Reason obtains the aceted intermediate；
Shown in the structure of the aceted intermediate such as formula (II):
In formula (I)~(II), DMG is selected from-CON-R、-CONR2、Wherein, R is selected from C1~C5Alkyl, most preferably
For isopropyl.
Reaction equation is as follows:
DMG:-CON-R、-CONR2、Deng；
Preferably, the organometallic reagent is alkyl lithium compounds or Grignard Reagent in step (1)；As into
One step it is preferred, the organometallic reagent is n-BuLi or TMPMgClLiCl.
Preferably, reaction temperature is -70~30 DEG C in step (1) and step (2).
Preferably, the reaction dissolvent of step (1) is that ether solvent is directly added into reaction solution after reaction is completed
The acetylation reagent enters step the reaction of (2).
As a further preference, the ether solvent is tetrahydrofuran, ether or Isosorbide-5-Nitrae-dioxane etc..
In step (2), the acetylation reagent that the acylating reagent can be common for this field, such as N, N- dimethyl second
Amide, 4- acetylmorpholine or acetate compounds, preferably, the acylating reagent is N, N- diformazan in step (2)
Yl acetamide or 4- acetylmorpholine, good using these acylating reagent reaction effects, reaction yield is high, and side reaction is few.
Preferably, the acylating reagent is n,N-dimethylacetamide in step (2)；
The reaction dissolvent of step (2) is the mixed solvent of tetrahydrofuran and toluene；
The volume ratio of tetrahydrofuran and toluene is 1:0.5~2.The inventors discovered that when using n,N-dimethylacetamide
As reaction dissolvent, when using mixed solvent as reaction reagent, acylation reaction yield is higher, and acylating reagent cost compared with
It is low, it is convenient for industrialized production.
Preferably, the post-processing includes: that dilute hydrochloric acid is added to reaction solution to be quenched, solvent evaporated, mistake in step (2)
Filter is recrystallized to give the aceted intermediate.
As a further preference, recrystallizing solvent used is methanol or ethyl alcohol.
Compared with the existing technology, the beneficial effects of the present invention are embodied in:
(1) method of the invention reduces environmental pollution while improving product quality quality, clean production,
Environmental protection makes product be more suitable for producing in enormous quantities.
(2) ortho position homing device of the present invention has very strong coordination or chelating effect, leads to the acidity of ortho-hydrogens
Enhancing, convenient for pulling out hydrogen, obtained ortho position metal intermediates can be reacted with various electrophilic reagents, and the DMG of obtained product can be with
It restores, is converted into other groups, or directly remove.
Specific embodiment
The present invention is further explained in the light of specific embodiments, but protection scope of the present invention is not limited in
This.
Embodiment 1
(1) in the four-hole boiling flask equipped with thermometer, blender, it is molten in the water of 3 times of volumes that 1.2mol potassium carbonate is added
Xie Hou is added into 5 times of weight of toluene and the N of 1.2mol, N- diisopropylamine reaction solution, opens stirring, controls reaction temperature
10-20 DEG C, start to be added dropwise 1.0mol to fluorobenzoyl chloride, after reacting 2h, by reaction solution liquid separation, organic phase is spin-dried for obtaining intermediate
A, yield 95%, purity 99%.
The structure of intermediate a is as follows:
Nuclear magnetic data:1H NMR(400MHz,CDCl3):δ7.29-7.34(m,2H),7.04-7.10(m,2H),3.67(s,
2H),1.33(s,12H)ppm；
(2) toward 4 times of weight THF solutions of intermediate a, start the n-BuLi THF solution that 1.2mol is added dropwise, control temperature
At -70~-60 DEG C, after about reaction 1h, it is added drop-wise in 1.0mol n,N-dimethylacetamide and 1 times of weight THF solution, drips
2h is kept the temperature after adding 0.5h, dilute hydrochloric acid is added dropwise to and is quenched, reaction solution is spin-dried for, is filtered, is recrystallized with 3 times of weight percent methanols, just
Aceted intermediate 1 can be obtained.Yield 64.6%, purity 99.12%.
The structure of aceted intermediate 1 is as follows:
1H NMR(400MHz,CDCl3): δ 7.48 (dd, J=2.4,9.0Hz, 1H), 7.22 (ddd, J=2.4,8.4,
16.0Hz, 1H), 7.21 (dd, J=9.0,16.0Hz, 1H), 3.46-3.60 (m, 2H), 2.59 (s, 3H), 1.58 (d, J=
7.2Hz, 6H), 1.13 (d, J=7.2Hz, 6H) ppm.
Embodiment 2
(1) in the four-hole boiling flask equipped with thermometer, blender, it is molten in the water of 3 times of volumes that 1.2mol potassium carbonate is added
Xie Hou is added into 5 times of weight of toluene and the N of 1.2mol, N- diisopropylamine reaction solution, opens stirring, controls reaction temperature
10-20 DEG C, starts dropwise addition 1.0mol and fluorobenzoyl chloride, by reaction solution liquid separation, is spin-dried for obtaining intermediate a, yield after reacting 2h
95%, purity 99%.
(2) toward 4 times of weight THF solutions of intermediate a, start the n-BuLi THF solution that 1.2mol is added dropwise, control temperature
At -70~-60 DEG C, after about reaction 1h, reaction solution is added drop-wise to 1.4mol n,N-dimethylacetamide and 1 times of weight THF is molten
In liquid, 2h is kept the temperature after 0.5h is added dropwise, dilute hydrochloric acid is added dropwise to and is quenched, reaction solution is spin-dried for, filtered, with 3 times of weight percent methanol weights
Crystallization, can obtain aceted intermediate 1.Yield 70.6%, purity 99.15%.
Embodiment 3
(1) in the four-hole boiling flask equipped with thermometer, blender, it is molten in the water of 3 times of volumes that 1.2mol potassium carbonate is added
Xie Hou is added into 5 times of weight of toluene and the N of 1.2mol, N- diisopropylamine reaction solution, opens stirring, controls reaction temperature
10-20 DEG C, starts dropwise addition 1.0mol and fluorobenzoyl chloride, by reaction solution liquid separation, is spin-dried for obtaining intermediate a, yield after reacting 2h
95%, purity 99%.
(2) toward 4 times of weight THF solutions of intermediate a, start the n-BuLi THF solution that 1.2mol is added dropwise, control temperature
At -70~-60 DEG C, after about reaction 1h, it is added drop-wise in 1.8mol n,N-dimethylacetamide and 1 times of weight THF solution, drips
2h is kept the temperature after adding 0.5h, dilute hydrochloric acid is added dropwise to and is quenched, reaction solution is spin-dried for, is filtered, is recrystallized with 3 times of weight percent methanols, just
Aceted intermediate 1 can be obtained.Yield 70.8%, purity 99.13%.
Examples 1 to 3 the result shows that, the dosage increase of n,N-dimethylacetamide can improve yield, but work as N, N-
When the dosage of dimethyl acetamide increases to 1.6mol, it is further added by the dosage of n,N-dimethylacetamide, yield improves unobvious.
Therefore select 1.6mol DMAC N,N' dimethyl acetamide as acetylation reagent.
Embodiment 4
The 4- acetylmorpholine of 1.6mol is used to replace n,N-dimethylacetamide as acetylation reagent, other conditions and reality
It is identical to apply example 2, yield 86.3%, purity 99.3%.
Embodiment 5
The chloroacetic chloride of 1.6mol is used to replace n,N-dimethylacetamide as acetylation reagent, other conditions and embodiment 2
It is identical, yield 58.5%, purity 94.32%.
Embodiment 6
Toward 2 times of weight THF and 2 times of toluene solutions of intermediate a (1.0mol), start the n-BuLi that 1.2mol is added dropwise
THF solution controls temperature at -50~-40 DEG C, after about reaction 1h, is added drop-wise to 1.6mol n,N-dimethylacetamide and 1 times
In weight THF solution, 2h is kept the temperature after 0.5h is added dropwise, dilute hydrochloric acid is added dropwise to and is quenched, reaction solution is spin-dried for, filtered, with 3 times of weights
Recrystallizing methanol is measured, aceted intermediate 1 can be obtained.Yield 81.8%, purity 99.2%.
Embodiment 7
(1) in the four-hole boiling flask equipped with thermometer, blender, it is molten in the water of 3 times of volumes that 1.2mol potassium carbonate is added
Xie Hou is added into the toluene of 5 times of weight and 2- amino-2-methyl-propyl alcohol reaction solution of 1.2mol, opens stirring, control
10-20 DEG C of reaction temperature, starts dropwise addition 1.0mol and fluorobenzoyl chloride, by reaction solution liquid separation, is spin-dried for obtaining centre after reacting 2h
Body b, yield 92%, purity 99.3%.
The structure of intermediate b is shown below:
1H NMR(400Hz,CDCl3):δ7.88(m,2H),7.00(m,2H),4.05(s,2H),1.30(s,6H)ppm.
(2) TMPMgClLiCl of 1.2mol (2.5M in THF) is dissolved in 3 times of weight THF, controls temperature in 25-
30 DEG C, 3 times of weight THF solutions of intermediate b are added drop-wise to, after about reaction 1h, reaction solution is added drop-wise to 1.4mol N, N- diformazan
Yl acetamide and 2 times of weight THF solutions keep the temperature 2h after 0.5h is added dropwise, are added dropwise to dilute hydrochloric acid and are quenched, reaction solution is spin-dried for,
Filtering is recrystallized with 3 times of w ethanols, can obtain aceted intermediate 2.Yield 70.7%, purity 99.11%.
Shown in the structure following formula of aceted intermediate 2:
1H NMR(400Hz,CDCl3):δ7.83(m,2H),7.05(m,2H),4.14(s,2H),2.59(s,3H),1.20
(s,6H)ppm.
Embodiment 8
(1) in the four-hole boiling flask equipped with thermometer, blender, it is molten in the water of 3 times of volumes that 1.2mol potassium carbonate is added
Xie Hou is added into the toluene of 5 times of weight and 2- amino-2-methyl-propyl alcohol reaction solution of 1.2mol, opens stirring, control
10-20 DEG C of reaction temperature, starts dropwise addition 1.0mol and fluorobenzoyl chloride, by reaction solution liquid separation, is spin-dried for obtaining centre after reacting 2h
Body b, yield 92%, purity 99.3%.
(2) TMPMgClLiCl of 1.2mol (2.5M in THF) is dissolved in 3 times of weight THF, controls temperature in 25-
30 DEG C, 3 times of weight THF solutions of intermediate b are added drop-wise to, after about reaction 1h, reaction solution is added drop-wise to 1.6mol N, N- diformazan
Yl acetamide and 2 times of weight THF solutions keep the temperature 2h after 0.5h is added dropwise, are added dropwise to dilute hydrochloric acid and are quenched, reaction solution is spin-dried for,
Filtering is recrystallized with 3 times of w ethanols, can obtain aceted intermediate 2.Yield 73.5%, purity 99.14%.
Embodiment 9
(1) in the four-hole boiling flask equipped with thermometer, blender, it is molten in the water of 3 times of volumes that 1.2mol potassium carbonate is added
Xie Hou is added into 2- amino-2-methyl-propyl alcohol reaction solution of 5 times of weight of toluene and 1.2mol, opens stirring, and control is anti-
10-20 DEG C of temperature is answered, starts dropwise addition 1.0mol and fluorobenzoyl chloride, by reaction solution liquid separation, is spin-dried for obtaining intermediate after reacting 2h
B, yield 92%, purity 99.3%.
(2) TMPMgClLiCl of 1.2mol (2.5M in THF) is dissolved in 3 times of weight THF, controls temperature in 25-
30 DEG C, 3 times of weight THF solutions of intermediate b are added drop-wise to, after about reaction 1h, reaction solution is added drop-wise to 1.8mol N, N- diformazan
Yl acetamide and 2 times of weight THF solutions keep the temperature 2h after 0.5h is added dropwise, are added dropwise to dilute hydrochloric acid and are quenched, reaction solution is spin-dried for,
Filtering is recrystallized with 3 times of w ethanols, can obtain aceted intermediate 2.Yield 73.8%, purity 99.15%.
Embodiment 10
1.6mol 4- acetylmorpholine is attempted as acetylation reagent, other conditions are same as Example 7, yield difference
It is 83.2%, purity is respectively 99.13%.
Embodiment 8~10 the result shows that, the dosage increase of n,N-dimethylacetamide can improve yield, but work as N, N-
When the dosage of dimethyl acetamide increases to 1.6mol, it is further added by the dosage of n,N-dimethylacetamide, yield improves unobvious.
Therefore select 1.6mol DMAC N,N' dimethyl acetamide as acetylation reagent.
Claims (10)
1. the preparation method of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of one kind (S) -5-, which is characterized in that
The following steps are included:
(1) fluorine arene compounds are reacted with organometallic reagent, obtains ortho position metal intermediates；
Shown in structure to the fluorine arene compounds such as formula (I):
(2) the ortho position metal intermediates that step (1) obtains react with acetylation reagent, after the reaction was completed after post treatment
To the aceted intermediate；
Shown in the structure of the aceted intermediate such as formula (II):
In formula (I)~(II), DMG is selected from-CON-R、-CONR2、Wherein, R is selected from C1~C5Alkyl.
2. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 1
Method, which is characterized in that in step (1), the organometallic reagent is alkyl lithium compounds or Grignard Reagent.
3. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 2
Method, which is characterized in that the organometallic reagent is n-BuLi or TMPMgClLiCl.
4. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 1
Method, which is characterized in that in step (1) and step (2), reaction temperature is -70~25 DEG C.
5. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 1
Method, which is characterized in that the reaction dissolvent of step (1) is ether solvent, after reaction is completed, directly into reaction solution described in addition
Acetylation reagent enter step the reaction of (2).
6. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 5
Method, which is characterized in that the ether solvent is tetrahydrofuran, ether or Isosorbide-5-Nitrae-dioxane.
7. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 1
Method, which is characterized in that in step (2), the acylating reagent is n,N-dimethylacetamide or 4- acetylmorpholine.
8. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 1
Method, which is characterized in that in step (2), the acylating reagent is n,N-dimethylacetamide；
The reaction dissolvent of step (2) is the mixed solvent of tetrahydrofuran and toluene；
The volume ratio of tetrahydrofuran and toluene is 1:0.5~2.
9. the preparation side of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 1
Method, which is characterized in that in step (2), the post-processing includes: that dilute hydrochloric acid is added to reaction solution to be quenched, solvent evaporated, filtering,
It is recrystallized to give the aceted intermediate.
10. the preparation of the aceted intermediate of the fluoro- 3- methyl isobenzofuran -3- ketone of (S) -5- according to claim 9
Method, which is characterized in that recrystallizing solvent used is methanol or ethyl alcohol.
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| US20160013426A1 (en) * | 2013-03-28 | 2016-01-14 | Fujifilm Corporation | Photoelectric conversion element, imaging device, optical sensor, and method of using photoelectric conversion element |
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| US20160013426A1 (en) * | 2013-03-28 | 2016-01-14 | Fujifilm Corporation | Photoelectric conversion element, imaging device, optical sensor, and method of using photoelectric conversion element |
Non-Patent Citations (2)
| Title |
|---|
| L. BRANDSMA等: "Dimetallation of phenylacetylene.Synthesis of ortho-substituted derivatives of phenylacetylene, benzo[ blselenophene and benzo[b]tellurophene", 《RED. TRAV. CHIM. PAYS-BAS》 * |
| SHENGQUAN DUAN等: "Developing an Asymmetric Transfer Hydrogenation Process for (S)‑5-Fluoro-3-methylisobenzofuran-1(3H)‑one,a Key Intermediate to Lorlatinib", 《ORG.PROCESSRES.DEV.》 * |
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