CN105153105A - Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate - Google Patents

Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate Download PDF

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CN105153105A
CN105153105A CN201510502205.4A CN201510502205A CN105153105A CN 105153105 A CN105153105 A CN 105153105A CN 201510502205 A CN201510502205 A CN 201510502205A CN 105153105 A CN105153105 A CN 105153105A
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CN105153105B (en
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叶天健
陆修伟
郁光亮
何思
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Zhejiang Yongning Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety

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Abstract

The invention belongs to the field of chemical synthesis of drugs, particularly relates to a synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and an intermediate and aims to provide a synthesis method of a compound (1). The method comprises steps as follows: a, a compound (4) and boron tribromide react, and a compound (3) is synthesized; b, the compound (3) and difluorodibromomethane have a ring closing reaction in the presence of a phase-transfer catalyst, and a compound (2) is synthesized; c, the compound (2) is hydrolyzed, and the compound (1) is synthesized. According to the synthetic method and the intermediate, one novel compound (4) is provided, one novel preparation method of the compound (1) is obtained, with the adoption of the method, not only can the overall yield of the reaction be increased, but also expensive reaction raw materials can be avoided, and the reaction cost is reduced to the great extent; besides, according to the method, utilization of a palladium catalyst and a dangerous sodium cyanide reagent can further be avoided, the safety of pharmaceutical production is guaranteed, and the method is applicable to industrial production.

Description

The synthetic method of 1-(2,2-difluoro benzo [d] [1,3] dioxole-5-base) cyclopropane-carboxylic acid and intermediate thereof
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, be specifically related to synthetic method and the intermediate thereof of a kind of 1-(2,2-difluoro benzo [d] [1,3] dioxole-5-base) cyclopropane-carboxylic acid.
Background technology
Cystic fibrosis (CF) is a kind of heredopathia of serious threat life, and this disease system is caused by the defect of CF transmembrane conductance regulator (CFTR).Normal CFTR is a kind of chloride channel protein be present on cytolemma, and chlorion frees in and out cell by this channel protein, and cell also can secrete the thin mucus of one deck to protect airway epithelia.And the cftr gene of the CF patient of 90% there will be the F508del sudden change disappearance of 508 phenylalanines (in the CFTR), there is this sudden change, CFTR just can not normally fold, it is very easily degraded after composition, cause the CFTR quantity on cell significantly to reduce, chlorion can not be freed in and out equally.Cystic fibrosis is very common America and Europe, and almost 25 people just there will be a case.Just have 22 in the U.S., 000 patient of more than 12 years old is because two kinds of copy F508del transgenation caused.
Lu Makat (Lumacaftor) researches and develops by Vertex drugmaker the medicine being used for the treatment of cystic fibrosis diseases, Vertex have submitted the application for quotation of a compound medicine be made up of Lu Makat (Lumacaftor) and Yi Wakate (Ivacaftor) completely respectively to US and European, and obtaining FDA approval in July, 2015, this compound medicine is that first is to carry the medicine that the basic cause of disease of transgenation patient cystic fibrosis of two kinds of copy F508del is target spot.
1-(2,2-difluoro benzo [d] [1,3] dioxole-5-base) cyclopropane-carboxylic acid is an intermediate of synthesis lumacaftor, and its structural formula is as shown in compound (1):
Disclose the synthetic method about 1-(2,2-difluoro benzo [d] [1,3] dioxole-5-base) cyclopropane-carboxylic acid in patent CN101356170, concrete synthetic route is as follows:
There is following defect in this route: 1. reaction raw materials is expensive, is unfavorable for controlling cost; 2. use palladium catalyst in reaction process, in product, easily have palladium to remain; 3. the sodium cyanide reagent used in reaction is more dangerous, is unsuitable for suitability for industrialized production; 4. react overall yield very low.
Summary of the invention
In order to solve the problem, the invention provides synthetic method and the intermediate thereof of 1-(2,2-difluoro benzo [d] [1, the 3] dioxole-5-base) cyclopropane-carboxylic acid that a kind of cost is low, yield is high, easy to operate.
An object of the present invention is to provide the synthetic method of a kind of compound (1), described method comprises:
A. compound (4) and boron tribromide Reactive Synthesis compound (3)
B. compound (3) and difluorodibromomethane carry out ring closure reaction synthetic compound (2) in the presence of a phase transfer catalyst
C. compound (2) hydrolysis compound (1)
Wherein, R 1, R 2or R 3it is alkyl.
Preferably, described R 1, R 2or R 3be selected from methyl, ethyl or propyl group arbitrarily; Preferred, R 1, R 2or R 3it is methyl;
The temperature of reaction of described step a is-20-15 DEG C, preferably-10-10 DEG C;
The reaction of described step a is carried out in the conventional organic solvents such as halogenated hydrocarbon solvent, alcoholic solvent, ether solvent, preferably carries out in methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or ethyl acetate, more preferably carries out in methylene dichloride or tetrahydrofuran (THF).
The phase-transfer catalyst of described step b is selected from the conventional phase-transfer catalysts such as benzyltriethylammoinium chloride (TEBA), Tetrabutyl amonium bromide (TBAB), tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, preferred Tetrabutyl amonium bromide (TBAB);
In described step b, the mol ratio of compound and difluorodibromomethane is 1:3-1:10, preferred 1:4-1:5, more preferably 1:5;
Described step b reacts under weak base participates in, described weak base preferred alkali metal carbonate or alkali metal hydrocarbonate, more preferably salt of wormwood, sodium carbonate, saleratus or sodium bicarbonate;
The temperature of reaction of described step b is 80-120 DEG C, preferred 90-100 DEG C;
Described step b carries out in high boiling organic solvent, described high boiling organic solvent refers to that boiling point is higher than the organic solvent of 100 DEG C, such as be selected from N-pyrrolidone (NMP), N, dinethylformamide (DMF), N, the conventional high boiling organic solvents such as N-N,N-DIMETHYLACETAMIDE (DMAC), dimethyl sulfoxide (DMSO) (DMSO) or toluene, preferably at N-pyrrolidone, N, carry out in dinethylformamide or dimethyl sulfoxide (DMSO) (DMSO), more preferably carry out in dimethyl sulfoxide (DMSO) (DMSO).
Described step c carries out in strong base solution, described highly basic preferred alkali metal hydroxide, more preferably sodium hydroxide or potassium hydroxide.
Further, the synthetic method of above-claimed cpd (1) also comprises the synthesis of compound (4), and concrete steps are as follows:
D. compound (7) is through esterification synthetic compound (6)
E. compound (6) and polyformaldehyde reaction synthetic compound (5)
F. compound (5) and Trimethylsulfoxonium Iodide synthetic compound (4) under organic bases participates in
Wherein, R 1, R 2or R 3it is alkyl.
Preferably, described R 1, R 2or R 3be selected from methyl, ethyl or propyl group arbitrarily; Preferred, R 1, R 2or R 3it is methyl;
The esterification of described steps d is preferably carried out under carbonyl dimidazoles participates in;
The reaction of described steps d is carried out in the conventional organic solvents such as halogenated hydrocarbon solvent, alcoholic solvent, ether solvent, preferably carries out in methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or ethyl acetate, more preferably carries out in methylene dichloride, tetrahydrofuran (THF).
In described step e, compound (6) is 1:5-1:15 with the mol ratio of paraformaldehyde, preferred 1:8-1:10, more preferably 1:10.
Described step e carries out under weak base participates in, described weak base preferred alkali metal carbonate or alkali metal hydrocarbonate, more preferably sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus;
Described step e carries out in the conventional organic solvents such as ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, preferably carries out in tetrahydrofuran (THF), methylene dichloride, toluene, more preferably carries out in tetrahydrofuran (THF);
In described step f, compound (5) is 1:1.5-1:3.0 with the mol ratio of Trimethylsulfoxonium Iodide, preferred 1:2.0.
Organic bases in described step f is selected from the conventional organic basess such as sodium alkoxide, potassium alcoholate or amido lithium compound, particular methanol sodium, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, lithium diisopropylamine (LDA), hexamethyldisilazane lithium (LiHMDS) or hmds base potassium (KHMDS), more preferably potassium tert.-butoxide.
The reaction solvent of described step f can be selected from N, dinethylformamide (DMF), N, the conventional organic solvents such as N-N,N-DIMETHYLACETAMIDE (DMAC), dimethyl sulfoxide (DMSO) (DMSO), toluene, preferred N, dinethylformamide (DMF) or N, N-N,N-DIMETHYLACETAMIDE (DMAC), more preferably DMF (DMF).
Another object of the present invention is to provide compound shown in a kind of formula (4), and its structure is:
Wherein, R 1, R 2or R 3it is alkyl.
Preferably, described R 1, R 2, R 3be selected from methyl, ethyl or propyl group arbitrarily; Preferred, R 1, R 2or R 3it is methyl.
Another object of the present invention is to provide the synthetic method of a kind of compound (4), specifically comprises the steps:
D. compound (7) is through esterification synthetic compound (6)
E. compound (6) and polyformaldehyde reaction synthetic compound (5)
F. compound (5) and Trimethylsulfoxonium Iodide synthetic compound (4) under organic bases participates in
Wherein, R 1, R 2or R 3it is alkyl.
Preferably, described R 1, R 2or R 3be selected from methyl, ethyl or propyl group arbitrarily; Preferred, R 1, R 2or R 3it is methyl;
The esterification of described steps d is preferably carried out under carbonyl dimidazoles participates in;
The reaction of described steps d is carried out in the conventional organic solvents such as halogenated hydrocarbon solvent, alcoholic solvent, ether solvent, preferably carries out in methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or ethyl acetate, more preferably carries out in methylene dichloride, tetrahydrofuran (THF).
In described step e, compound (6) is 1:5-1:15 with the mol ratio of paraformaldehyde, preferred 1:8-1:10, more preferably 1:10.
Described step e carries out under weak base participates in, described weak base preferred alkali metal carbonate or alkali metal hydrocarbonate, more preferably sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus;
Described step e carries out in the conventional organic solvents such as ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, preferably carries out in tetrahydrofuran (THF), methylene dichloride, toluene, more preferably carries out in tetrahydrofuran (THF);
In described step f, compound (5) is 1:1.5-1:3.0 with the mol ratio of Trimethylsulfoxonium Iodide, preferred 1:2.0.
Organic bases in described step f is selected from the conventional organic basess such as sodium alkoxide, potassium alcoholate or amido lithium compound, particular methanol sodium, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, lithium diisopropylamine (LDA), hexamethyldisilazane lithium (LiHMDS) or hmds base potassium (KHMDS), more preferably potassium tert.-butoxide.
The reaction solvent of described step f can be selected from N, dinethylformamide (DMF), N, the conventional organic solvents such as N-N,N-DIMETHYLACETAMIDE (DMAC), dimethyl sulfoxide (DMSO) (DMSO), toluene, preferred N, dinethylformamide (DMF) or N, N-N,N-DIMETHYLACETAMIDE (DMAC), more preferably DMF (DMF).
The present invention is by providing a kind of new compound (4), obtain a kind of method preparing compound (1) newly, this method can not only improve the overall yield of reaction, can avoid using expensive reaction raw materials simultaneously, reduce the cost of reaction to a great extent.On the other hand, this method can also be avoided using palladium catalyst and dangerous sodium cyanide reagent, guarantees the security of pharmaceutical production, is applicable to suitability for industrialized production.
Embodiment
Set forth the present invention further below in conjunction with specific embodiment, should be understood that following examples are only not used in for illustration of the present invention and limit the scope of the invention.
In the following example, method therefor if no special instructions, is ordinary method.Material required in following examples or reagent, be market if no special instructions and buy.
Embodiment 1: the synthesis of compound 6a
Compound 7a (50g, 0.255mol) is added, 250ml methylene dichloride in the there-necked flask of 1L, stirring at room temperature, adds carbonyl dimidazoles (62g, 0.382mol) in batches, room temperature reaction 1h, adds 50ml methyl alcohol, stirs 1h, reaction solution is poured in separating funnel, add the extraction of 200ml water, collected organic layer, anhydrous sodium sulfate drying, filter, filtrate decompression is spin-dried for, obtain 50g compound 6a, yield 93.3%.
Embodiment 2: the synthesis of compound 5a
To in 250mL there-necked flask, add compound 6a (10g, 0.048mol), 80ml tetrahydrofuran (THF), add paraformaldehyde (15g, 0.48mol) successively, salt of wormwood (20g, 0.144mol), 40 DEG C of reaction 2h.After reacting completely, poured into by reaction solution in separating funnel, add 100ml water respectively, 150ml tetrahydrofuran (THF) extracts, collected organic layer, anhydrous sodium sulfate drying, and filter, filtrate decompression is spin-dried for, and obtains 9.6g compound 5a, yield 90.0%.
Embodiment 3: the synthesis of compound 4a
Under the protection of nitrogen, in 250ml round-bottomed flask, add Trimethylsulfoxonium Iodide (44.0g, 0.2mol), 100mlDMF, then add potassium tert.-butoxide (22.3g, 0.2mol), stirring at room temperature 45min.Be dissolved in 70mlDMF by compound 5a (22.2g, 0.1mol), add in above-mentioned solution slowly, reaction system is warming up to 35 DEG C.Be heated to 45 DEG C, reaction 1h, makes reaction system be cooled to 0-5 DEG C, drips 80ml2N hydrochloric acid soln, adds 250ml extraction into ethyl acetate water layer, anhydrous sodium sulfate drying, and filter, filtrate decompression is spin-dried for, and obtains 20.8g compound 4a, yield 88.1%.1HNMR(400MHz,DMSO)6.90(d,J＝1.7Hz,H),6.87–6.82(m,2H),3.74(s,3H),3.74(s,3H),3.54(s,3H),1.45(q,J＝3.8Hz,2H),1.17(q,J＝4.0Hz,2H).
Embodiment 4: the synthesis of compound 4a
To in 250ml there-necked flask, add compound 6a (21.0g, 0.1mol), 80ml tetrahydrofuran (THF), add paraformaldehyde (31.3g, 1mol) successively, salt of wormwood (41.7g, 0.3mol), 40 DEG C of reaction 2h.After reacting completely, reaction solution is poured in constant pressure funnel.Under the protection of nitrogen, in 250ml round-bottomed flask, add Trimethylsulfoxonium Iodide
(44.0g, 0.2mol), 100mlDMF, then add potassium tert.-butoxide (22.3g, 0.2mol), stirring at room temperature 45min, added slowly in round-bottomed flask by the solution in constant pressure funnel, reaction system is warming up to 35 DEG C.Be heated to 45 DEG C, reaction 1h, makes reaction system be cooled to 0-5 DEG C, drips 80ml2N hydrochloric acid soln, adds 250ml extraction into ethyl acetate water layer, anhydrous sodium sulfate drying, and filter, filtrate decompression is spin-dried for, and obtains 20.4g, yield 86.4% after being spin-dried for.
Embodiment 5: the synthesis of compound 3a
Under the protection of nitrogen; compound 4a (9g is added in 250ml round-bottomed flask; 0.038mol); 50ml methylene dichloride; be cooled to-20 DEG C, drip boron tribromide (21g, 0.084mol) slowly; holding temperature is-10 DEG C; reaction 1h, add 10ml methyl alcohol slowly, system acutely heats up; holding temperature is lower than 15 DEG C; return to reduced pressure at room temperature to be spin-dried for, add 40ml methyl alcohol and continue to be spin-dried for, take away the HBr in system and trimethyl borate; 7.3g compound 3a is obtained, yield 92.4% after being spin-dried for.
Embodiment 6: the synthesis of compound 2a
In the autoclave pressure of 100ml, add compound 3a (4.2g, 0.02mol), difluorodibromomethane (9.1ml, 0.1mol), salt of wormwood (3.3g, 0.024mol), TBAB (0.3g, 0.04mol), DMSO (30ml), is heated to 100 DEG C of reactions.After reacting completely, system is down to room temperature, is added by reaction solution in 100ml trash ice and stirs, separate organic layer, anhydrous sodium sulfate drying, and filter, filtrate decompression is spin-dried for, and obtains 4.7g compound 2a, yield 91.8%.
Embodiment 7: the synthesis of compound 1
Compound 2a (3.3g, 0.013mol) is added in 100ml there-necked flask, 20ml5%NaOH solution, be heated to 85 DEG C, reaction 2h.After reacting completely, regulate pH=7, add 30ml extraction into ethyl acetate, anhydrous sodium sulfate drying, filter, filtrate decompression is spin-dried for, and obtains 3.0g compound 1, yield 95.2%.
Embodiment 8: the synthesis of compound 6b
Compound 7b (64.3g, 0.255mol) is added, 250ml methylene dichloride in the there-necked flask of 1L, stirring at room temperature, adds carbonyl dimidazoles (62g, 0.382mol) in batches, room temperature reaction 1h, adds 50ml methyl alcohol, stirs 1h, reaction solution is poured in separating funnel, add the extraction of 200ml water, collected organic layer, anhydrous sodium sulfate drying, filter, filtrate decompression is spin-dried for, obtain 60.4g compound 6b, yield 89.0%.
Embodiment 9: the synthesis of compound 5a
According to the embodiment of embodiment 2, study when the molar ratio that compound 6a and paraformaldehyde feed intake is different on the impact of reacting, and Real-Time Monitoring response situation, the charging capacity of compound 6a is 0.048mol, and reaction result is as shown in the table:
Compound 6a: paraformaldehyde Output Yield
1:2 6.0g 56％
1:5 7.5g 70％
1:8 9.0g 84％
1:10 9.6g 90％
1:13 9.5g 89％
1:15 9.3g 87％
1:17 6.5g 61％
Embodiment 10: the synthesis of compound 4a
According to the embodiment of embodiment 3, study when the molar ratio that compound 5a and Trimethylsulfoxonium Iodide feed intake is different on the impact of reacting, and Real-Time Monitoring response situation, the charging capacity of compound 5a is 0.1mol, and reaction result is as shown in the table:
Compound 5a: Trimethylsulfoxonium Iodide Output Yield
1:1.2 9.0g 38.1％
1:1.5 17.7g 75.0％
1:2.0 20.8g 88.1％
1:2.5 20.7g 87.7％
1:3.0 20.8g 88.1％
Embodiment 11: the synthesis of compound 2a
According to the embodiment of embodiment 6, the change of the molar ratio that research compound 3a and difluorodibromomethane feed intake and temperature of reaction is on the impact of reaction yield.Individually change mol ratio and the temperature of reaction of compound 3a and difluorodibromomethane, remaining reaction condition with embodiment 6, Real-Time Monitoring response situation, result is as shown in the table:

Claims (10)

  1. The synthetic method of 1.1-(2,2-difluoro benzo [d] [1,3] dioxole-5-base) cyclopropane-carboxylic acid, is characterized in that, comprise the steps:
    A. compound 4 and boron tribromide Reactive Synthesis compound 3
    B. compound 3 and difluorodibromomethane carry out ring closure reaction synthetic compound 2 in the presence of a phase transfer catalyst
    C. compound 2 hydrolysis compound 1
    Wherein, R 1, R 2or R 3it is alkyl.
  2. 2. method according to claim 1, is characterized in that, in described step b, compound 3 is 1:3-1:10 with the mol ratio of difluorodibromomethane.
  3. 3. method according to claim 1, is characterized in that, the phase-transfer catalyst of described step b is Tetrabutyl amonium bromide.
  4. 4. method according to claim 1, is characterized in that, the temperature of reaction of described step b is 80-120 DEG C.
  5. 5. method according to claim 1, is characterized in that, described compound 4 is synthesized by following step:
    D. compound 7 is through esterification synthetic compound 6
    E. compound 6 and polyformaldehyde reaction synthetic compound 5
    F. compound 5 and Trimethylsulfoxonium Iodide synthetic compound 4 under organic bases participates in
    Wherein, R 1, R 2or R 3it is alkyl.
  6. 6. compound shown in formula 4 described in claim 1
    Wherein, R 1, R 2or R 3it is alkyl.
  7. 7. the synthetic method of compound 4 described in claim 1, is characterized in that, described method comprises the steps:
    D. compound 7 is through esterification synthetic compound 6
    E. compound 6 and polyformaldehyde reaction synthetic compound 5
    F. compound 5 and Trimethylsulfoxonium Iodide synthetic compound 4 under organic bases participates in
    Wherein, R 1, R 2or R 3it is alkyl.
  8. 8. the method according to claim 5 or 7, is characterized in that, in described step e, compound 6 is 1:5-1:15 with the mol ratio of paraformaldehyde.
  9. 9. the method according to claim 5 or 7, is characterized in that, in described step f, compound 5 is 1:1.5-1:3.0 with the mol ratio of Trimethylsulfoxonium Iodide.
  10. 10. the method according to claim 5 or 7 is characterized in that, the organic bases in described step f is potassium tert.-butoxide.
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