CN105153105B - The synthetic method and its intermediate of 1 (base of 2,2 difluoro benzo [d] [1,3] dioxole 5) cyclopropane-carboxylic acid - Google Patents

The synthetic method and its intermediate of 1 (base of 2,2 difluoro benzo [d] [1,3] dioxole 5) cyclopropane-carboxylic acid Download PDF

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CN105153105B
CN105153105B CN201510502205.4A CN201510502205A CN105153105B CN 105153105 B CN105153105 B CN 105153105B CN 201510502205 A CN201510502205 A CN 201510502205A CN 105153105 B CN105153105 B CN 105153105B
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compound
reaction
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synthetic method
cyclopropane
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CN105153105A (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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    • C—CHEMISTRY; METALLURGY
    • 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

Abstract

The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of synthetic method and its intermediate of 1 (base of 2,2 difluoro benzo [d] [1,3] dioxole 5) cyclopropane-carboxylic acid.It is an object of the present invention to provide a kind of synthetic method of compound (1), methods described includes：A. compound (4) and Boron tribromide reaction synthesis compound (3)B. compound (3) carries out ring closure reaction with difluorodibromomethane and synthesizes compound (2) in the presence of a phase transfer catalystC. compound (2) hydrolysis compound (1)

Description

1- (2,2- difluoros benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid Synthetic method and its intermediate
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of 1- (2,2- difluoro benzo [d] [1,3] dioxas Cyclopentene -5- bases) cyclopropane-carboxylic acid synthetic method and its intermediate.
Background technology
Cystic fibrosis (CF) is a kind of genetic disease of serious threat life, and the disease adjusts egg by CF transmembrane conductors It is caused the defects of (CFTR) in vain.Normal CFTR is a kind of chloride channel protein being present on cell membrane, and chlorion can Cell is freed in and out by this channel protein, cell can also secrete one layer of thin mucus to protect airway epithelia.And 90% The cftr gene of CF patient occurs that F508del is mutated (missing of 508 phenylalanines in CFTR), and this mutation occurs, CFTR cannot be folded normally, and it is easily degraded after composition, cause the CFTR quantity on cell to be greatly decreased so that chlorine Ion can not equally free in and out.Cystic fibrosis is very common in America and Europe, and almost a case just occurs in 25 people.In U.S. It is due to caused by two kinds of copy F508del gene mutations that, which just there are 22,000 patients of more than 12 years old in state,.
Lu Makat (Lumacaftor) is that the medicine for treating cystic fibrosis diseases is researched and developed by Vertex drugmakers Thing, Vertex have submitted to US and European a completely by Lu Makat (Lumacaftor) and Yi Wakate respectively (Ivacaftor) application for quotation of the compound medicine of composition, and FDA approvals are obtained in July, 2015, this compound medicine is first Using medicine of the basic cause of disease of gene mutation patient's cystic fibrosis as target spot for carrying two kinds of copy F508del.
1- (2,2- difluoros benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid is synthesis lumacaftor One intermediate, shown in its structural formula such as compound (1)：
Disclosed in patent CN101356170 on 1- (2,2- difluoros benzo [d] [1,3] dioxole -5- bases) The synthetic method of cyclopropane-carboxylic acid, specific synthetic route are as follows：
Following defect be present in the route：1. reaction raw materials are expensive, it is unfavorable for control cost；2. palladium chtalyst is used in course of reaction Agent, easily there is palladium residual in product；3. the cyaniding sodium reagent used in reaction is relatively hazardous, it is unsuitable for industrialized production；4. reaction Overall yield is very low.
The content of the invention
In order to solve the above problems, the invention provides a kind of cost is low, high income, easy to operate 1- (2,2- difluoros Benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid synthetic method and its intermediate.
It is an object of the present invention to provide a kind of synthetic method of compound (1), methods described includes：
A. compound (4) and Boron tribromide reaction synthesis compound (3)
B. compound (3) carries out ring closure reaction with difluorodibromomethane and synthesizes compound in the presence of a phase transfer catalyst (2)
C. compound (2) hydrolysis compound (1)
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2Or R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl；
The reaction temperature of the step a is -20-15 DEG C, preferably -10-10 DEG C；
The reaction of the step a is carried out in the conventional organic solvent such as halogenated hydrocarbon solvent, alcohols solvent, ether solvent, It is preferred that carried out in dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, more preferably in dichloromethane or tetrahydrofuran Middle progress.
The phase transfer catalyst of the step b be selected from benzyltriethylammoinium chloride (TEBA), TBAB (TBAB), The conventional phase transfer catalyst such as tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, preferably TBAB (TBAB)；
Compound and the mol ratio of difluorodibromomethane are 1 in the step b:3-1:10, preferably 1:4-1:5, more preferably 1:5；
The step b is reacted in weak base presence, the weak base preferred alkali metal carbonate or alkali metal hydrogen carbonate Salt, more preferably potassium carbonate, sodium carbonate, saleratus or sodium acid carbonate；
The reaction temperature of the step b is 80-120 DEG C, preferably 90-100 DEG C；
The step b is carried out in high boiling organic solvent, and the high boiling organic solvent refers to that boiling point is higher than 100 DEG C Organic solvent, it is selected from N- pyrrolidones (NMP), DMF (DMF), DMA (DMAC), the conventional high boiling organic solvent such as dimethyl sulfoxide (DMSO) (DMSO) or toluene, preferably in N- pyrrolidones, N, N- dimethyl Carry out in formamide or dimethyl sulfoxide (DMSO) (DMSO), more preferably carried out in dimethyl sulfoxide (DMSO) (DMSO).
The step c is carried out in strong base solution, the highly basic preferred alkali metal hydroxide, more preferably sodium hydroxide or Potassium hydroxide.
Further, the synthetic method of above-claimed cpd (1) also includes the synthesis of compound (4), comprises the following steps that：
D. compound (7) synthesizes compound (6) through esterification
E. compound (6) synthesizes compound (5) with polyformaldehyde reaction
F. compound (5) synthesizes compound (4) with Trimethylsulfoxonium Iodide in organic base presence
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2Or R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl；
The esterification of the step d is preferably carried out in carbonyl dimidazoles presence；
The reaction of the step d is carried out in the conventional organic solvent such as halogenated hydrocarbon solvent, alcohols solvent, ether solvent, It is preferred that carried out in dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, more preferably in dichloromethane, tetrahydrofuran Carry out.
Compound (6) and the mol ratio of paraformaldehyde are 1 in the step e:5-1:15, preferably 1:8-1:10, more preferably 1:10。
The step e is carried out in weak base presence, the weak base preferred alkali metal carbonate or alkali metal hydrogencarbonate, more It is preferred that sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；
The step e is carried out in the conventional organic solvent such as ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, preferably Carry out in tetrahydrofuran, dichloromethane, toluene, carried out more preferably in tetrahydrofuran；
Compound (5) and the mol ratio of Trimethylsulfoxonium Iodide are 1 in the step f:1.5-1:3.0, preferably 1:2.0.
Organic base in the step f is selected from the conventional organic bases, preferably methanol such as sodium alkoxide, potassium alcoholate or amido lithium compound Sodium, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine (LDA), hexamethyldisilazane lithium (LiHMDS) or six The silicon amido potassium (KHMDS) of methyl two, more preferably potassium tert-butoxide.
The reaction dissolvent of the step f can be selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAC), the conventional organic solvent such as dimethyl sulfoxide (DMSO) (DMSO), toluene, preferably DMF (DMF) or N, N- bis- Methylacetamide (DMAC), more preferably DMF (DMF).
It is a further object of the present invention to provide compound, its structure shown in a kind of formula (4) to be：
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2、R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl.
It is yet another object of the invention to provide a kind of synthetic method of compound (4), specifically comprise the following steps：
D. compound (7) synthesizes compound (6) through esterification
E. compound (6) synthesizes compound (5) with polyformaldehyde reaction
F. compound (5) synthesizes compound (4) with Trimethylsulfoxonium Iodide in organic base presence
Wherein, R1、R2Or R3It is alkyl.
Preferably, the R1、R2Or R3Arbitrarily it is selected from methyl, ethyl or propyl group；It is furthermore preferred that R1、R2Or R3It is methyl；
The esterification of the step d is preferably carried out in carbonyl dimidazoles presence；
The reaction of the step d is carried out in the conventional organic solvent such as halogenated hydrocarbon solvent, alcohols solvent, ether solvent, It is preferred that carried out in dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, more preferably in dichloromethane, tetrahydrofuran Carry out.
Compound (6) and the mol ratio of paraformaldehyde are 1 in the step e:5-1:15, preferably 1:8-1:10, more preferably 1:10。
The step e is carried out in weak base presence, the weak base preferred alkali metal carbonate or alkali metal hydrogencarbonate, more It is preferred that sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；
The step e is carried out in the conventional organic solvent such as ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, preferably Carry out in tetrahydrofuran, dichloromethane, toluene, carried out more preferably in tetrahydrofuran；
Compound (5) and the mol ratio of Trimethylsulfoxonium Iodide are 1 in the step f:1.5-1:3.0, preferably 1:2.0.
Organic base in the step f is selected from the conventional organic bases, preferably methanol such as sodium alkoxide, potassium alcoholate or amido lithium compound Sodium, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine (LDA), hexamethyldisilazane lithium (LiHMDS) or six The silicon amido potassium (KHMDS) of methyl two, more preferably potassium tert-butoxide.
The reaction dissolvent of the step f can be selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAC), the conventional organic solvent such as dimethyl sulfoxide (DMSO) (DMSO), toluene, preferably DMF (DMF) or N, N- bis- Methylacetamide (DMAC), more preferably DMF (DMF).
The present invention obtains a kind of method of new prepare compound (1) by providing a kind of new compound (4), this Method can not only improve the overall yield of reaction, while can avoid, using expensive reaction raw materials, largely reducing The cost of reaction.On the other hand, this method is also avoided that using palladium catalyst and dangerous cyaniding sodium reagent, it is ensured that medicine The security of production, it is adapted to industrialized production.
Embodiment
The present invention is expanded on further with reference to specific embodiment, it should be appreciated that following examples are merely to illustrate the present invention Rather than limit the scope of the invention.
Method therefor is conventional method unless otherwise instructed in the following example.Material required in following examples Material or reagent, are that market is bought unless otherwise specified.
Embodiment 1：Compound 6a synthesis
Compound 7a (50g, 0.255mol) is added into 1L there-necked flask, 250ml dichloromethane, is stirred at room temperature, in batches Secondary addition carbonyl dimidazoles (62g, 0.382mol), react at room temperature 1h, add 50ml methanol, stir 1h, and reaction solution is poured into point In liquid funnel, the extraction of 200ml water is added, collected organic layer, anhydrous sodium sulfate drying, is filtered, filtrate decompression is spin-dried for, and obtains 50gization Compound 6a, yield 93.3%.
Embodiment 2：Compound 5a synthesis
Into 250mL there-necked flasks, compound 6a (10g, 0.048mol) is added, 80ml tetrahydrofurans, sequentially adds poly Formaldehyde (15g, 0.48mol), potassium carbonate (20g, 0.144mol), 40 DEG C of reaction 2h.After reaction completely, reaction solution is poured into liquid separation In funnel, 100ml water, the extraction of 150ml tetrahydrofurans, collected organic layer, anhydrous sodium sulfate drying, filtering, filtrate are separately added into Decompression is spin-dried for, and obtains 9.6g compound 5a, yield 90.0%.
Embodiment 3：Compound 4a synthesis
Under the protection of nitrogen, Trimethylsulfoxonium Iodide (44.0g, 0.2mol) is added into 250ml round-bottomed flasks, 100ml DMF, potassium tert-butoxide (22.3g, 0.2mol) is added, 45min is stirred at room temperature.By compound 5a (22.2g, 0.1mol) It is dissolved in 70ml DMF, slowly adds in above-mentioned solution, reaction system is warming up to 35 DEG C.45 DEG C are heated to, reacts 1h, is made anti- Answer system to be cooled to 0-5 DEG C, 80ml 2N hydrochloric acid solutions are added dropwise, add 250ml ethyl acetate aqueous layer extracteds, anhydrous sodium sulfate is done Dry, filtering, filtrate decompression is spin-dried for, and obtains 20.8g compound 4a, yield 88.1%.1H NMR (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：Compound 4a synthesis
Into 250ml there-necked flasks, compound 6a (21.0g, 0.1mol) is added, 80ml tetrahydrofurans, sequentially adds poly Formaldehyde (31.3g, 1mol), potassium carbonate (41.7g, 0.3mol), 40 DEG C of reaction 2h.After reaction completely, reaction solution is poured into constant pressure In dropping funel.Under the protection of nitrogen, Trimethylsulfoxonium Iodide is added into 250ml round-bottomed flasks
(44.0g, 0.2mol), 100ml DMF, potassium tert-butoxide (22.3g, 0.2mol) is added, 45min is stirred at room temperature, Solution in constant pressure funnel is slowly added in round-bottomed flask, reaction system is warming up to 35 DEG C.45 DEG C are heated to, reaction 1h, reaction system is cooled to 0-5 DEG C, 80ml 2N hydrochloric acid solutions are added dropwise, add 250ml ethyl acetate aqueous layer extracteds, anhydrous sulphur Sour sodium is dried, and filtering, filtrate decompression is spin-dried for, and 20.4g, yield 86.4% are obtained after being spin-dried for.
Embodiment 5：Compound 3a synthesis
Under the protection of nitrogen, compound 4a (9g, 0.038mol), 50ml dichloromethanes are added into 250ml round-bottomed flasks Alkane, -20 DEG C are cooled to, Boron tribromide (21g, 0.084mol) is slowly added dropwise, it is -10 DEG C to maintain temperature, reacts 1h, slowly Add 10ml methanol, system acutely heats up, maintains temperature below 15 DEG C, recover to reduced pressure at room temperature to be spin-dried for, add 40ml methanol after It is continuous to be spin-dried for, the HBr and trimethylborate in system are taken away, 7.3g compound 3a, yield 92.4% are obtained after being spin-dried for.
Embodiment 6：Compound 2a synthesis
In 100ml autoclave pressure, addition compound 3a (4.2g, 0.02mol), difluorodibromomethane (9.1ml, 0.1mol), potassium carbonate (3.3g, 0.024mol), TBAB (0.3g, 0.04mol), DMSO (30ml), 100 DEG C of reactions are heated to. After reaction completely, system is down to room temperature, and reaction solution is added in 100ml trash ices and stirred, separates organic layer, anhydrous sodium sulfate is done Dry, filtering, 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 flasks, 20ml 5%NaOH solution, is heated to 85 DEG C, react 2h.After reaction completely, pH=7 is adjusted, adds the extraction of 30ml ethyl acetate, anhydrous sodium sulfate drying, filtering, filtrate Decompression is spin-dried for, and obtains 3.0g compounds 1, yield 95.2%.
Embodiment 8：Compound 6b synthesis
Compound 7b (64.3g, 0.255mol) is added into 1L there-necked flask, 250ml dichloromethane, is stirred at room temperature, point Batch adds carbonyl dimidazoles (62g, 0.382mol), reacts at room temperature 1h, adds 50ml methanol, stirs 1h, reaction solution is poured into In separatory funnel, the extraction of 200ml water, collected organic layer are added, anhydrous sodium sulfate drying filters, and filtrate decompression is spin-dried for, obtained 60.4g compound 6b, yield 89.0%.
Embodiment 9：Compound 5a synthesis
According to the embodiment of embodiment 2, study when the molar ratio difference that compound 6a and paraformaldehyde feed intake pair The influence of reaction, and monitor response situation in real time, compound 6a inventory are 0.048mol, reaction result such as following table institute Show：
Compound 6a：Paraformaldehyde Yield 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：Compound 4a synthesis
According to the embodiment of embodiment 3, the molar ratio that research is fed intake with Trimethylsulfoxonium Iodide as compound 5a is not Influence to reaction simultaneously, and monitor response situation in real time, compound 5a inventory are 0.1mol, reaction result such as following table It is shown：
Compound 5a：Trimethylsulfoxonium Iodide Yield 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：Compound 2a synthesis
According to the embodiment of embodiment 6, molar ratio that research compound 3a feeds intake with difluorodibromomethane and anti- The change of temperature is answered to the influence of reaction yield.Individually change mol ratio and the reaction of compound 3a and difluorodibromomethane Temperature, remaining reaction condition monitors response situation with embodiment 6 in real time, as a result as shown in the table：

Claims (8)

  1. The synthetic method of 1.1- (2,2- difluoro benzo [d] [1,3] dioxole -5- bases) cyclopropane-carboxylic acid, its feature exist In comprising the following steps：
    A. compound 4 and Boron tribromide reaction synthesis compound 3
    B. compound 3 carries out ring closure reaction with difluorodibromomethane and synthesizes compound 2 in the presence of a phase transfer catalyst
    C. the hydrolysis compound 1 of compound 2
    Wherein, R1、R2Or R3It is alkyl；The reaction temperature of the step a is -10-10 DEG C；Compound 3 and two in the step b The mol ratio of difluorodibromomethane is 1:4-1:5；The reaction temperature of the step b is 80-120 DEG C.
  2. 2. according to the method for claim 1, it is characterised in that the phase transfer catalyst of the step b is tetrabutyl phosphonium bromide Ammonium.
  3. 3. according to the method for claim 1, it is characterised in that the compound 4 is synthesized by following step：
    D. compound 7 synthesizes compound 6 through esterification
    E. compound 6 synthesizes compound 5 with polyformaldehyde reaction
    F. compound 5 synthesizes compound 4 with Trimethylsulfoxonium Iodide in organic base presence
    Wherein, R1、R2Or R3It is alkyl.
  4. 4. compound shown in formula 4 described in claim 1
    Wherein, R1、R2Or R3It is alkyl.
  5. 5. the synthetic method of compound 4 described in claim 1, it is characterised in that methods described comprises the following steps：
    D. compound 7 synthesizes compound 6 through esterification
    E. compound 6 synthesizes compound 5 with polyformaldehyde reaction
    F. compound 5 synthesizes compound 4 with Trimethylsulfoxonium Iodide in organic base presence
    Wherein, R1、R2Or R3It is alkyl.
  6. 6. the method according to claim 3 or 5, it is characterised in that compound 6 and paraformaldehyde rubs in the step e Your ratio is 1:5-1:15.
  7. 7. the method according to claim 3 or 5, it is characterised in that compound 5 and trimethyl iodate are sub- in the step f The mol ratio of sulfone is 1:1.5-1:3.0.
  8. 8. the method according to claim 3 or 5 is characterized in that, the organic base in the step f is potassium tert-butoxide.
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