WO2000076947A1 - Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene - Google Patents
Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene Download PDFInfo
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- WO2000076947A1 WO2000076947A1 PCT/US2000/015735 US0015735W WO0076947A1 WO 2000076947 A1 WO2000076947 A1 WO 2000076947A1 US 0015735 W US0015735 W US 0015735W WO 0076947 A1 WO0076947 A1 WO 0076947A1
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- acid
- bιs
- acetic acid
- sulfuπc
- tπfluoromethyl
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- CSVCVIHEBDJTCJ-UHFFFAOYSA-N FC(c1cc(C(F)(F)F)cc(Br)c1)(F)F Chemical compound FC(c1cc(C(F)(F)F)cc(Br)c1)(F)F CSVCVIHEBDJTCJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
Definitions
- the present invention relates to processes for the preparation of 3,5- b ⁇ s(t ⁇ fluoromethyl)bromobenzene (CAS 328-70-1) which is useful as an intermediate in the preparation of certain therapeutic agents
- the present invention provides a process for the preparation of 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurok ⁇ n ⁇ n-1) receptor antagonists
- the use of acetic acid and/or a faster rate of stirring for the bromination of l,3-b ⁇ s(t ⁇ fluoromethyl)benzene in sulfu ⁇ c acid results in a more selective bromination of the starting ate ⁇ al with higher yields of the product and lower amounts of bis-brominated byproducts.
- 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene is an important intermediate for a particularly useful class of therapeutic agents
- there is a need for the development of a process for the preparation of 3,5-b ⁇ s- (t ⁇ fluoromethyl)bromobenzene which is readily amenable to scale-up, uses cost- effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
- the subject invention provides a process for the preparation of 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene via a very simple, short and highly efficient synthesis.
- novel process of this invention involves the synthesis of 3,5- b ⁇ s(t ⁇ fluoromethyl)bromobenzene.
- present invention is concerned with novel processes for the preparation of a compound of the formula:
- This compound is an intermediate in the synthesis of compounds which possess pharmacological activity
- such compounds are substance P (neurok ⁇ n ⁇ n-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiat ⁇ c disorders, and emesis.
- the present invention is directed to processes for the preparation of 3,5-b ⁇ s(trifluoromethyl)bromobenzene of the formula-
- the present invention is directed to the preparation of 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene by the reaction of 1,3-b ⁇ s- (t ⁇ fluoromethyl)benzene with l,3-d ⁇ bromo-5,5-d ⁇ methylhydanto ⁇ n in a mixture composing glacial acetic acid and 96% sulfu ⁇ c acid
- the use of acetic acid and/or a high rate of mixing in this reaction system increases solubilization of the starting mate ⁇ al and results in less sensitivity to stir ⁇ ng parameters, as well as increased regioselectivity with respect to the position of bromination.
- An embodiment of the present invention concerns a process for the preparation of 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene of the formula:
- a preferred embodiment within the present invention concerns a process for the preparation of 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene of the formula
- brominatmg agent selected from N-bromosuccinimide and 1,3- d ⁇ bromo-5,5-d ⁇ methylhydantom, to give 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene
- N-bromosuccinimide ⁇ BS
- DBH l,3-d ⁇ bromo-5,5-d ⁇ methylhydanto ⁇ n
- l,3-d ⁇ bromo-5,5-d ⁇ methylhydantom is more preferred
- the preferred solvent system is a mixture of sulfu ⁇ c acid and acetic acid, and a more preferred solvent system is a mixture of concentrated sulfu ⁇ c acid and glacial acetic acid
- the ratio of sulfu ⁇ c acid acetic acid is approximately 5 1 to 7T (v:v), and it is more preferred that the ratio of sulfu ⁇ c acid'acetic acid is approximately 6:1 (v:v)
- the sulfu ⁇ c acid is added to the acetic acid at a controlled rate with cooling and rapidly mixing (such as with mechanical stir ⁇ ng)
- the ratio of the sulfu ⁇ c acid/ acetic acid to the l,3-b ⁇ s(t ⁇ fluoromethyl)benzene substrate is approximately 2 1 to 1.2 (vv).
- the ratio of the sulfu ⁇ c acid/acetic acid to the l,3-b ⁇ s(t ⁇ fluoromethyl)benzene substrate is approximately 1.5: 1 (v:v).
- the l,3-b ⁇ s(t ⁇ fluoromethyl)- benzene is added to the sulfu ⁇ c ac ⁇ d:acet ⁇ c acid at a controlled rate with cooling and rapidly mixing (such as with mechanical stir ⁇ ng).
- the reaction mixture is rapidly mixed (such as with mechanical stir ⁇ ng) and cooled upon treatment with the brominatmg agent
- the brominatmg agent is added to rapidly mixed reaction mixture which comprises sulfu ⁇ c acid, acetic acid, and l,3-b ⁇ s(t ⁇ fluoromethyl)benzene.
- the brominatmg agent is added to the reaction mixture in a controlled manner as individual portions.
- the preferred temperature range following addition of the brominatmg agent is between about 10 and 70°C, a more prefered reaction temperature range is between about 40 and 50°C, and the most preferred temperature is about 45 ° C
- l,3-b ⁇ s(t ⁇ fluoromethyl)benzene is brommated with N,N'-d ⁇ bromo-5,5-d ⁇ methylhydanto ⁇ n in sulfu ⁇ c acid/acetic acid at 45 °C
- the reaction mixture is then diluted into cold water, and the phases are separated, washed with aqueous sodium hydroxide (preferably 5N sodium hydroxide) and allowed to separate to produce 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene
- the product may contain approximately 2.6% lsome ⁇ c impu ⁇ ties (which typically include l,2-d ⁇ bromo-3,5-b ⁇ s(t ⁇ fluoromethyl)benzene, 1,4-d ⁇ bromo- 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene, as well as small amounts of 2,4-b ⁇ s(t ⁇ fluoro- methyl)bromobenzene, 2,6-b ⁇ s(t ⁇ fluoromethyl)bromobenzene, and 3,5- b ⁇ s(t ⁇ fluoromethyl)b ⁇ phenyl
- the 3,5-b ⁇ s(t ⁇ fluoromethyl)bromobenzene obtained in accordance with the present invention may be used directly without distillation as starting mate ⁇ al in further reactions.
- the rate and selectivity of the bromination is highly dependent on the agitation of the two phase reaction. Slower stirnng increases the amount of bis- brommation and slows the overall rate of reaction.
- the rate of bromination is also dependent on the ratio of acetic to sulfu ⁇ c acid. Progress of the reaction is monitored by GC analysis, as follows Sample- -50 ⁇ l of mixed phase, dilute with cyclohexane (1.5 mL), wash with water (1 mL), then 2N NaOH (1 mL), separate and inject.
- the assay yield of l,3-b ⁇ s(tnfluoromethyl)bromobenzene was 93 7% (137.3 g, 469 mmol), which contained 0.6% l,3-b ⁇ s(t ⁇ fluoromethyl)benzene, 1 0% l,2-d ⁇ bromo-3,5-b ⁇ s(t ⁇ fluoromethyl)benzene, and 0.3% l,4-d ⁇ bromo-3,5-b ⁇ s-
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Abstract
The present invention is concerned with a novel process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene (CAS 328-70-1). This compound is useful as an intermediate in the synthesis of compounds which possess pharmacological activity.
Description
TITLE OF THE INVENTION
PROCESS FOR THE SYNTHESIS OF 3,5-BIS(TRIFLUOROMETHYL)-
BROMOBENZENE
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of 3,5- bιs(tπfluoromethyl)bromobenzene (CAS 328-70-1) which is useful as an intermediate in the preparation of certain therapeutic agents In particular the present invention provides a process for the preparation of 3,5-bιs(tπfluoromethyl)bromobenzene which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokιnιn-1) receptor antagonists
The preparation of 3,5-bιs(tπfluoromethyl)bromobenzene by bromination of l,3-bιs(tπfluoromethyl)benzene has been descπbed various refeiences See for example (a) Porwisiak, J, Schlosser, M Chem Ber , 129(2), 233 (1996), (b) Kunshenko, B V , Omarov, V O , Muratov, N N , Mikhailevskn, S M ,
Yagupol'skπ, L M Zh Org Khun , 27(1), 125 (1991), (c) Laπonova, Y A , Ponomarev, A I , Klebanskn, A L , Zaitsev, N B , Kol'tsov, A I , Motsarev, G V , Rozenberg, V R Zh Pnkl Khun „ 46(9), 2012 (1973), (d) Furumata, T (Central Glass Company, Ltd ) JP 9067297-A2 [J09067297] 97 03 11 , Filing Date 08/28/95, (e) Suzuki, H (Nissan Chemical Industries, Ltd , Japan) JP 9169673-A2 [J09169673] 97 06 30 Heisei, Filing Date 12/22/95 These references descπbe the preparation of 3,5-bιs(tπfluoromethyl)bromobenzene by brominating l,3-bιs(tπfluoromethyl)- benzene utilizing either N-bromosuccimmide (ΝBS) or 1,3 dιbromo-5,5-dιmethyl- hydantom (DBH) in sulfuπc acid or tπfluoroacetic acid The yields are quoted in the 90% range with isomeπc and bis brominated byproducts amounting to 5-10%
Efforts to repeat the procedures using methods with sulfuπc acid as disclosed therein led to inconsistent yields of the desired product
The general processes disclosed in the art for the preparation of 3,5- bιs(tπfluoromethyl)bromobenzene result in relatively low and inconsistent yields of the desired product In contrast to the previously known processes, the present invention provides effective methodology for the preparation of 3,5-bιs(tπfluoro- methyl)bromobenzene in relatively higher yield
In accordance with the present invention, the use of acetic acid and/or a faster rate of stirring for the bromination of l,3-bιs(tπfluoromethyl)benzene in
sulfuπc acid results in a more selective bromination of the starting ateπal with higher yields of the product and lower amounts of bis-brominated byproducts.
It will be appreciated that 3,5-bιs(tπfluoromethyl)bromobenzene is an important intermediate for a particularly useful class of therapeutic agents As such, there is a need for the development of a process for the preparation of 3,5-bιs- (tπfluoromethyl)bromobenzene which is readily amenable to scale-up, uses cost- effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of 3,5-bιs(tπfluoromethyl)bromobenzene via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of 3,5- bιs(tπfluoromethyl)bromobenzene. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula:
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity In particular, such compounds are substance P (neurokιnιn-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatπc disorders, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of 3,5-bιs(trifluoromethyl)bromobenzene of the formula-
In a highly preferred embodiment, the present invention is directed to the preparation of 3,5-bιs(tπfluoromethyl)bromobenzene by the reaction of 1,3-bιs- (tπfluoromethyl)benzene with l,3-dιbromo-5,5-dιmethylhydantoιn in a mixture composing glacial acetic acid and 96% sulfuπc acid
In accordance with the present invention, the use of acetic acid and/or a high rate of mixing in this reaction system increases solubilization of the starting mateπal and results in less sensitivity to stirπng parameters, as well as increased regioselectivity with respect to the position of bromination.
An embodiment of the present invention concerns a process for the preparation of 3,5-bιs(tπfluoromethyl)bromobenzene of the formula:
which compπses. treating a reaction mixture which comprises sulfuπc acid, acetic acid, and l,3-bιs(tπfluoromethyl)benzene of the formula:
A preferred embodiment within the present invention concerns a process for the preparation of 3,5-bιs(tπfluoromethyl)bromobenzene of the formula
which compπses treating a reaction mixture which comprises concentrated sulfuπc acid, glacial acetic acid, and l,3-bιs(tπfluoromethyl)benzene of the formula
with a brominatmg agent selected from N-bromosuccinimide and 1,3- dιbromo-5,5-dιmethylhydantom, to give 3,5-bιs(tπfluoromethyl)bromobenzene
Although numerous brominatmg agents may be employed in this process, N-bromosuccinimide (ΝBS) and l,3-dιbromo-5,5-dιmethylhydantoιn (DBH) are preferred, and l,3-dιbromo-5,5-dιmethylhydantom is more preferred
This process is earned out in a solvent which compπses sulfuπc acid and acetic acid, and which may additionally compπse water The preferred solvent system is a mixture of sulfuπc acid and acetic acid, and a more preferred solvent system is a mixture of concentrated sulfuπc acid and glacial acetic acid In the present invention it is preferred that the ratio of sulfuπc acid acetic acid is approximately 5 1 to 7T (v:v), and it is more preferred that the ratio of sulfuπc acid'acetic acid is approximately 6:1 (v:v) In the present invention it is preferred that the sulfuπc acid is added to the acetic acid at a controlled rate with cooling and rapidly mixing (such as with mechanical stirπng)
In the present invention it is preferred that the ratio of the sulfuπc acid/ acetic acid to the l,3-bιs(tπfluoromethyl)benzene substrate is approximately 2 1 to 1.2 (vv). In the present invention it is more preferred that the ratio of the sulfuπc acid/acetic acid to the l,3-bιs(tπfluoromethyl)benzene substrate is approximately 1.5: 1 (v:v). In the present invention it is preferred that the l,3-bιs(tπfluoromethyl)- benzene is added to the sulfuπc acιd:acetιc acid at a controlled rate with cooling and rapidly mixing (such as with mechanical stirπng).
In the present invention it is preferred that the reaction mixture is rapidly mixed (such as with mechanical stirπng) and cooled upon treatment with the brominatmg agent In the present invention it is preferred that the brominatmg agent is added to rapidly mixed reaction mixture which comprises sulfuπc acid, acetic acid, and l,3-bιs(tπfluoromethyl)benzene. In the present invention it is also preferred that the brominatmg agent is added to the reaction mixture in a controlled manner as individual portions. The preferred temperature range following addition of the brominatmg agent is between about 10 and 70°C, a more prefered reaction temperature range is between about 40 and 50°C, and the most preferred temperature is about 45°C In a preferred embodiment, l,3-bιs(tπfluoromethyl)benzene is brommated with N,N'-dιbromo-5,5-dιmethylhydantoιn in sulfuπc acid/acetic acid at 45 °C The reaction mixture is then diluted into cold water, and the phases are separated, washed with aqueous sodium hydroxide (preferably 5N sodium hydroxide) and allowed to separate to produce 3,5-bιs(tπfluoromethyl)bromobenzene
The product may contain approximately 2.6% lsomeπc impuπties (which typically include l,2-dιbromo-3,5-bιs(tπfluoromethyl)benzene, 1,4-dιbromo- 3,5-bιs(tπfluoromethyl)bromobenzene, as well as small amounts of 2,4-bιs(tπfluoro- methyl)bromobenzene, 2,6-bιs(tπfluoromethyl)bromobenzene, and 3,5- bιs(tπfluoromethyl)bιphenyl
The 3,5-bιs(tπfluoromethyl)bromobenzene obtained in accordance with the present invention may be used directly without distillation as starting mateπal in further reactions.
None of the references cited above discuss problems associated with low rates of mixing, nor do they mention brominations in a mixture of acetic acid and sulfuπc acid. Surprisingly, in accordance with the present invention it was discovered that if the reaction is not stirred at an appropnate speed, the rate of bromination decreases, the yield of 3,5-bιs(tπfluoromethyl)bromobenzene drops, and production of
isomeπc, bis-brommated and tπs-brommated byproducts increases to upwards of 30% This indicates that more than one mechanism for the bromination reaction is operative in this system. Two reactions were performed on the same scale with N- bromosuccmimide (ΝBS) (1.05 eq) but at different stirrer speeds. The reactions were run in identical jacketed round bottom flasks, with identical stir bars and magnetic stirrers. The reaction rates differed as would be expected from a two-phase reaction, but the selectivity of the reactions were also different The slower stirnng reaction produced less product and more bis-brominated byproducts. Bromination of 1,3- bιs(tπfluoromethyl)benzene with N,N'-dιbromo-5,5-dιmethylhydantoιn (DBH) is similarly facilitated by the use of acetic acid and/or a higher rate of mixing Low stirnng of the reaction mixture leads to slower, less selective brommations, and this effect is ameliorated by the use of acetic acid.
The effect of excess amounts of DBH on the bromination in sulfuπc acid alone relative to the bromination in a combination of sulfuπc acid/acetic acid was examined. Using a 5 mol % excess of DBH (10 mol % excess Br+) at a slightly lower ratio of solvent: l,3-bιs(tπfluoromethyl)benzene (3.2: 1 v:v), the brominations were rapid. In sulfuπc acid alone, however, bis-bromination of 3,5-bιs(tπfluoro- methyl)bromobenzene continued after the starting matenal was completely consumed, whereas in sulfunc/acetic acid there was little or no loss to bis-bromination when 1,3- bιs(tnfluoromethyl)benzene was completely consumed Accordingly, the use of sulfunc acid/acetic acid avoids consumption of the product 3,5-bιs(tπfluoro- methyl)bromobenzene when excess brominatmg reagent is present.
Many of the starting matenals are either commercially available or known in the literature and others can be prepared following literature methods descnbed for analogous compounds. The skills required in carrying out the reaction and punfication of the resulting reaction products are known to those in the art. Punfication procedures include e.g., distillation, crystallization, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
EXAMPLE 1
3,5-Bιs(tnfluoromethyl)bromobenzene
To glacial acetic acid (22.0 mL), cooled to 15 °C in a 1 L 3-n RB flask (equipped with mechanical stirrer, thermocouple, and addition funnel), was added concentrated (96%) sulfunc acid (142 mL) in one portion An exothermic heat of solution raised the temperature to 35 °C After cooling to 25 °C, l,3-bιs(tπfluoro- methyl)benzene (107 g, 500 mmol) was added With the acid mixture rapidly stirnng, l,3-dιbromo-5,5-dιmethylhydantom (77.25 g, 270 mmol) was added over 2 mm to give a multiple phase mixture (solid and two liquid) An exothermic reaction occured that raised the internal temperature to -40 °C (jacket cooling at 15 °C) After the reaction temperature began to drop (after 5 mm) the reaction mixture was maintained at 45 °C for 4 5 hr
The rate and selectivity of the bromination is highly dependent on the agitation of the two phase reaction. Slower stirnng increases the amount of bis- brommation and slows the overall rate of reaction. The reaction mixture remains heterogeneous throughout the reaction and the organic phase separates when agitation is interrupted. At the end of the reaction, the phases separate slowly (bromide density = 1.699). The rate of bromination is also dependent on the ratio of acetic to sulfuπc acid.
Progress of the reaction is monitored by GC analysis, as follows Sample- -50 μl of mixed phase, dilute with cyclohexane (1.5 mL), wash with water (1 mL), then 2N NaOH (1 mL), separate and inject.
Resteck RTX-1701 [60 meter x 0.320 mm]- 100 °C; ramp: 5 °C/mιn to 200 °C; 200 °C for 10 min; Flow 1.15 mlJmin
Rt: l,3-bιs(tnfluoromethyl)benzene: 7.0 mm
3,5-bιs(tπfluoromethyl)bromobenzene: 9.4 mm
Biaryl: 19.2 mm
The mixture was cooled to 2 °C and poured slowly into cold water (250 mL). The mixture was stirred vigorously for 10 mm, allowed to settle, and the lower organic layer was separated and washed with 5N NaOH (75 mL) to give 145.1 g of a clear, colorless organic layer
The assay yield of l,3-bιs(tnfluoromethyl)bromobenzene was 93 7% (137.3 g, 469 mmol), which contained 0.6% l,3-bιs(tπfluoromethyl)benzene, 1 0% l,2-dιbromo-3,5-bιs(tπfluoromethyl)benzene, and 0.3% l,4-dιbromo-3,5-bιs-
(tπfluoromethyl)benzene. Total isomer byproducts measured by GC were 2.0 mol %.
While the invention has been descnbed and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that vanous adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above. Likewise, the specific reactivity of starting matenals may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected vaπations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims
1. A process for the preparation of a compound of the formula:
which comprises. treating a reaction mixture which compπses sulfuπc acid, acetic acid, and a compound of the formula-
with a brominatmg agent selected from' N-bromosuccinimide and 1,3- dιbromo-5,5-dιmethylhydantoιn, to give the compound of the formula
2 The process of Claim 1 wherein the brominatmg agents is l,3-dιbromo-5,5-dιmethylhydantoιn.
3. The process of Claim 1 wherein the reaction mixture compπses sulfunc acid and acetic acid.
4. The process of Claim 1 wherein the reaction mixture compπses concentrated sulfunc acid and glacial acetic acid.
5. The process of Claim 1 wherein the reaction mixture compnses sulfunc acid and acetic acid in which the ratio of sulfuπc acιd:acetιc acid is approximately 5:1 to 7:1 (v:v).
6. The process of Claim 5 wherein the reaction mixture compnses sulfuπc acid and acetic acid in which the ratio of sulfuπc acιd:acetιc acid is approximately 6: 1 (v:v).
7. The process of Claim 1 wherein the ratio of sulfunc acid/acetic acid to the substrate compound is approximately 2- 1 to 1:2 (v:v)
8 The process of Claim 7 wherein the ratio of sulfuπc acid/acetic acid to the substrate compound is approximately 1.5:1 (v:v).
9. The process of Claim 1 wherein the reaction mixture is rapidly mixed upon treatment with the brominatmg agent.
10. The process of Claim 1 wherein the brominatmg agent is added to a rapidly mixed reaction mixture which compπses sulfuπc acid, acetic acid, and 1 ,3-bιs(tnfluoromethyl)benzene.
11. The process of Claim 1 wherein the temperature range following addition of the brominatmg agent is between about 10 and 70°C.
12. The process of Claim 11 wherein the temperature range following addition of the brominatmg agent is between about 40 and 50°C.
13. The process of Claim 12 wherein the temperature following addition of the brominatmg agent is about 45°C.
14. A process for the preparation of 3,5-bιs(tπfluoromethyl)bromo- benzene which compnses contacting l,3-dιbromo-5,5-dιmethylhydantoιn with 1,3- bιs(tπfluoromethyl)benzene in a mixture compnsing acetic acid and sulfuπc acid to give 3,5-bιs(trifluoromethyl)bromobenzene.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001512364A JP2003505437A (en) | 1999-06-11 | 2000-06-08 | Synthesis process of 3,5-bis (trifluoromethyl) -bromobenzene |
| AU54725/00A AU5472500A (en) | 1999-06-11 | 2000-06-08 | Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene |
| EP20000939672 EP1192116A4 (en) | 1999-06-11 | 2000-06-08 | Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene |
| CA002374595A CA2374595A1 (en) | 1999-06-11 | 2000-06-08 | Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13888399P | 1999-06-11 | 1999-06-11 | |
| US33068499A | 1999-06-11 | 1999-06-11 | |
| US09/330,684 | 1999-06-11 | ||
| US60/138,883 | 1999-06-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000076947A1 true WO2000076947A1 (en) | 2000-12-21 |
Family
ID=26836648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2000/015735 WO2000076947A1 (en) | 1999-06-11 | 2000-06-08 | Process for the synthesis of 3,5-bis(trifluoromethyl)-bromobenzene |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1192116A4 (en) |
| JP (1) | JP2003505437A (en) |
| AU (1) | AU5472500A (en) |
| CA (1) | CA2374595A1 (en) |
| WO (1) | WO2000076947A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002024615A1 (en) * | 2000-09-23 | 2002-03-28 | Synprotec Limited | 1,3-bis(trifluoromethyl)benzene derivatives |
| US6814895B2 (en) | 2000-12-20 | 2004-11-09 | Merck & Co., Inc. | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one |
| CN110498729A (en) * | 2019-09-09 | 2019-11-26 | 武汉诺安药业有限公司 | A kind of clean method for preparing of hydrochloric acid Amorolfine intermediate |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4569002B2 (en) * | 2000-12-27 | 2010-10-27 | 住友化学株式会社 | Process for producing bromoaromatic condensed ring compound |
| CN1300076C (en) * | 2005-08-05 | 2007-02-14 | 上海康鹏化学有限公司 | Preparation method of double(2-hydroxyl hexafluopropyl) phenol |
| ITMI20060489A1 (en) * | 2006-03-17 | 2007-09-18 | Miteni Spa | PROCEDURE FOR THE PREPARATION OF 1-BEONO-3-TRIFLUOROMETOSSIBENZENE |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5502261A (en) * | 1994-03-23 | 1996-03-26 | Hoechst Aktiengesellschaft | Process for preparing 2,2'-bis(halomethyl)-1,1'-binaphthyl |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3806962B2 (en) * | 1995-12-22 | 2006-08-09 | 日産化学工業株式会社 | Method for producing 3,5-bis (trifluoromethyl) bromobenzene |
| GB0023383D0 (en) * | 2000-09-23 | 2000-11-08 | Synprotec Ltd | 3,5-Bis (Trifluormethyl)Benzene derivatives |
-
2000
- 2000-06-08 CA CA002374595A patent/CA2374595A1/en not_active Abandoned
- 2000-06-08 EP EP20000939672 patent/EP1192116A4/en not_active Withdrawn
- 2000-06-08 AU AU54725/00A patent/AU5472500A/en not_active Abandoned
- 2000-06-08 WO PCT/US2000/015735 patent/WO2000076947A1/en not_active Application Discontinuation
- 2000-06-08 JP JP2001512364A patent/JP2003505437A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5502261A (en) * | 1994-03-23 | 1996-03-26 | Hoechst Aktiengesellschaft | Process for preparing 2,2'-bis(halomethyl)-1,1'-binaphthyl |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP1192116A4 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002024615A1 (en) * | 2000-09-23 | 2002-03-28 | Synprotec Limited | 1,3-bis(trifluoromethyl)benzene derivatives |
| US6814895B2 (en) | 2000-12-20 | 2004-11-09 | Merck & Co., Inc. | Process for the synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one |
| CN110498729A (en) * | 2019-09-09 | 2019-11-26 | 武汉诺安药业有限公司 | A kind of clean method for preparing of hydrochloric acid Amorolfine intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5472500A (en) | 2001-01-02 |
| EP1192116A4 (en) | 2002-10-24 |
| CA2374595A1 (en) | 2000-12-21 |
| EP1192116A1 (en) | 2002-04-03 |
| JP2003505437A (en) | 2003-02-12 |
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