US20100145105A1 - Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof - Google Patents
Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof Download PDFInfo
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- US20100145105A1 US20100145105A1 US12/635,255 US63525509A US2010145105A1 US 20100145105 A1 US20100145105 A1 US 20100145105A1 US 63525509 A US63525509 A US 63525509A US 2010145105 A1 US2010145105 A1 US 2010145105A1
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- 0 [1*]CC1=CC(C([2*])([3*])O)=CC=C1[4*] Chemical compound [1*]CC1=CC(C([2*])([3*])O)=CC=C1[4*] 0.000 description 23
- FOQJHZPURACERJ-UHFFFAOYSA-N CB1OC(C)(C)C(C)(C)O1 Chemical compound CB1OC(C)(C)C(C)(C)O1 FOQJHZPURACERJ-UHFFFAOYSA-N 0.000 description 7
- GRJDNFSKEWOMIM-UHFFFAOYSA-N COC(=O)C1=CC=C(Br)C(CBr)=C1 Chemical compound COC(=O)C1=CC=C(Br)C(CBr)=C1 GRJDNFSKEWOMIM-UHFFFAOYSA-N 0.000 description 5
- GMZKNRDHSHYMHG-UHFFFAOYSA-N CC1=C(Br)C=C(O)C=C1 Chemical compound CC1=C(Br)C=C(O)C=C1 GMZKNRDHSHYMHG-UHFFFAOYSA-N 0.000 description 2
- UOQPLCPEHXFGSZ-UHFFFAOYSA-N O=C(OCC1=C(COC(=O)C2=CC=CC=C2)C=C(CBr)C=C1)C1=CC=CC=C1 Chemical compound O=C(OCC1=C(COC(=O)C2=CC=CC=C2)C=C(CBr)C=C1)C1=CC=CC=C1 UOQPLCPEHXFGSZ-UHFFFAOYSA-N 0.000 description 2
- DRKPCBJQZKMLLK-UHFFFAOYSA-N CCC(O)(CC)C1=CC=C(B(O)O)C(C)=C1 Chemical compound CCC(O)(CC)C1=CC=C(B(O)O)C(C)=C1 DRKPCBJQZKMLLK-UHFFFAOYSA-N 0.000 description 1
- VTEGNRZISAUGPR-UHFFFAOYSA-N CCC(O)(CC)C1=CC=C(Br)C(C)=C1 Chemical compound CCC(O)(CC)C1=CC=C(Br)C(C)=C1 VTEGNRZISAUGPR-UHFFFAOYSA-N 0.000 description 1
- GFDMVAVUQPFMHB-UHFFFAOYSA-N CCCC1=CC(C(=O)OC)=CC=C1Br Chemical compound CCCC1=CC(C(=O)OC)=CC=C1Br GFDMVAVUQPFMHB-UHFFFAOYSA-N 0.000 description 1
- VFVSMIHLZHGNHB-UHFFFAOYSA-N CCCC1=CC(C(O)(CC)CC)=CC=C1B(O)O Chemical compound CCCC1=CC(C(O)(CC)CC)=CC=C1B(O)O VFVSMIHLZHGNHB-UHFFFAOYSA-N 0.000 description 1
- UCMCMUPSXKKACG-UHFFFAOYSA-N CCCC1=CC(C(O)(CC)CC)=CC=C1B1OC(C)(C)C(C)(C)O1 Chemical compound CCCC1=CC(C(O)(CC)CC)=CC=C1B1OC(C)(C)C(C)(C)O1 UCMCMUPSXKKACG-UHFFFAOYSA-N 0.000 description 1
- MKHPLFWVYVUSLE-UHFFFAOYSA-N CCCC1=CC(C(O)(CC)CC)=CC=C1Br Chemical compound CCCC1=CC(C(O)(CC)CC)=CC=C1Br MKHPLFWVYVUSLE-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
- C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
Description
- This application is a divisional of U.S. application Ser. No. 11/454,859 filed Jun. 19, 2006 and claims priority under 35 U.S.C. §119 of FR 03/14946, filed Dec. 18, 2003, and is a continuation of PCT/FR 2004/003192, filed Dec. 10, 2004 which designates the United States (published in the French language on Jul. 7, 2005 as WO 2005/061520 A1; the title and abstract were also published in English), each hereby expressly incorporated by reference and each assigned to the assignee hereof.
- The present invention relates to novel disubstituted derivatives of phenylboronic acid, having the general formula (I):
- in which:
- R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
- R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms,
- R4 is the —B(OH)2 radical or the radical of formula:
- to processes for the preparation thereof and to their use as intermediates in the synthesis of non-steroidal vitamin D derivatives.
- Phenylboronic acid derivatives can be employed in Suzuki-type coupling reactions and are important intermediates in the synthesis of non-steroidal vitamin D3 analogues. Such reactions have been described by the assignee hereof in WO 03/050067.
- In WO 03/050067 the non-steroidal vitamin D derivatives of general formula (IVa) (see
FIG. 1 ) are obtained from intermediate triflates of general formula (5) and boronic acid intermediates of general formula (6). - The preparation of the intermediate triflates of general formula (5) involves 3 synthesis steps and that of the boronic acid intermediates of general formula (6) involves 6 synthesis steps.
- In the present invention the synthesis of the phenylboronic acids of general formula (Ia) takes place in 4 steps and involves the use of bromo derivatives of general formula (II) to obtain the non-steroidal vitamin D derivatives of general formula (IVa) according to
FIG. 2 . The bromo derivatives of general formula (II) are prepared in 3 steps. - The use of the phenylboronic acids of general formula (I) of the present invention therefore exhibits as its first advantage access to the biphenyl intermediates of general formula (III) in 7 steps in total (see
FIG. 2 ), whereas the synthesis described previously, in WO 03/050067, involves 9 steps for access to the biphenyl intermediates of general formula (7) (FIG. 1 ). - The use of the phenylboronic acids of general formula (I) involves the utilization of bromo derivatives of general formula (II), which exhibits as a second advantage the avoidance of the protection and deprotection steps required in order to prepare the boronic acid intermediates of general formula (6) that are used in the preceding synthesis (
FIG. 1 ). Moreover, the protection step was carried out with methoxymethyl chloride, a highly carcinogenic reactant which is prohibited on the industrial scale. - A third advantage provided by the use of the phenylboronic acids of general formula (I) is that they allow access to the biphenyl intermediates of general formula (III), in which the tertiary alcohol function is already present, whereas by proceeding via the biphenyl intermediates of general formula (7) as described in WO 03/050067 (
FIG. 1 ) it is still necessary to convert the ketone function into a tertiary alcohol function. - A fourth advantage provided by the use of the phenylboronic acids of general formula (I) is that they allow access to the non-steroidal vitamin D derivatives of general formula (IVa) in fewer steps than with the synthesis as described in WO 03/050067 and with a better yield.
- In the present invention novel phenylboronic acid derivatives have been synthesized via a novel process, which allows the above problems to be remedied.
- The present invention thus features novel disubstituted derivatives of phenylboronic acid, having the general formula (I):
- in which:
- R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
- R2 and R3, which may be identical or different, are each an alkyl radical having from of 1 to 4 carbon atoms, and
- R4 is the —B(OH)2 radical or the radical of formula:
-
FIGS. 1-4 illustrate a variety of reaction schemes for the ultimate preparation of the compounds of formula (I). - According to the present invention an alkyl radical having 1 to 4 carbon atoms is a saturated or unsaturated, linear or cyclic, optionally branched radical which contains 1 to 4 carbon atoms and can be interrupted by a heteroatom, and preferably the alkyl radicals having 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl or tert-butyl radicals.
- The present invention also features the following novel intermediate compounds:
- Where, for compounds (2) and (3), R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms and R5 is an alkyl radical having from 1 to 4 carbon atoms.
- The present invention likewise features employing the compounds (1), (2) and (3) for preparing non-steroidal vitamin D analogues and, in particular, as synthesis intermediates for preparing compounds of formula (I) according to the invention.
- This invention, therefore, also features a process for synthesizing the subject novel phenylboronic acid derivatives of formula (I).
- The synthesis of these novel phenylboronic acid compounds of general formula (I) in which R4 is the B(OH)2 radical is carried out in 4 steps starting from methyl 4-bromo-3-methylbenzoate (commercial product) according to the scheme of
FIG. 3 . - Therefore, the process for preparing compounds of general formula (I) in which R4 is the B(OH)2 radical comprises the following steps, steps a) and b) not being implemented in the specific case in which R1 is a hydrogen atom:
- a) bromination in the benzylic position in the presence of a solvent, to give the compound (1):
- b) substitution of the bromine introduced in step a) in the benzylic position by an alkyl chain R5 containing 1 to 4 carbon atoms, to give the compound (2) as defined above:
- c) conversion of the ester function of the intermediates of general formula (2) or of methyl 4-bromo-3-methylbenzoate into a tertiary alcohol function, using at least two equivalents of an organomagnesium compound of formula R2-MgX
- wherein X is a chlorine or bromine atom
- and R2 is a methyl, ethyl, propyl or butyl radical, to give the compound of general formula (3) as defined above:
- d) conversion of the aromatic bromide of the intermediates of general formula (3) into phenylboronic acid of formula (I) in the presence of a solvent, a base and a trialkyl borate.
- In greater detail, the steps of this process may be carried out as follows:
- a. The first step entails performing a bromination in the benzylic position to give the intermediate (1). This halogenation reaction is described in the literature. Various brominating agents may be used, such as, for example, bromine (K. Smith et al., J. Chem. Soc. Perkin. Trans., I, 2000, 2745), N-bromosuccinimide (P. Liu et al., Synthesis, 2001, 2078), sodium bromate (D. Kikuchi et al., J. Org. Chem., 1998, 6023) or else 1,3-dibromo-5,5-dimethylhydantoin (H. Jendralla et al., Liebigs Ann. Chem., 1995, 1253). This reaction is carried out most often in chlorinated solvents or in ethers. The brominating agent used with preference is N-bromosuccinimide at dichloromethane reflux. Preferably, benzoyl peroxide is also used, in a catalytic amount, as a free-radical reaction initiator. In order to activate the free-radical reaction the reaction mixture is irradiated with a 1000 watt lamp.
- This step provides the intermediate (1):
- b. The second step entails substituting the bromine introduced in
step 1 in the benzylic position by an alkylchain R′ 1 containing 1 to 4 carbon atoms. In order to promote this substitution reaction the nucleophilic character of the alkylgroup R′ 1 is increased by using an organometallic reagent R′1-M in which M is a metal atom such as magnesium, copper or else zinc. This reaction is described in the literature (B. H. Lipshutz and S. Sengupta, Organic Reactions, 1992, 41, 135). Preferably, copper in the form of copper iodide is employed in the presence of an organomagnesium compound R′1-MgX (X═Br, CI, I) in order to generate an organocuprate. This reaction may be carried out in ethereal solvents. Preferably the ethereal solvent used is tetrahydrofuran. The reaction is carried out at low temperature, preferably from −40° C. and 0° C., more particularly from −40° C. and −20° C. - This step provides the intermediates of general formula (2), the radicals of which are defined above.
- c. The third step entails converting the ester function of the intermediates of general formula (2) or of methyl 4-bromo-3-methylbenzoate into a tertiary alcohol function, using at least two equivalents of an organomagnesium compound of formula R2-MgX, wherein X is a chlorine, bromine or iodine atom and R2 is an alkyl radical having 1 to 4 carbon atoms. This reaction is widely described in the literature. This reaction may be carried out in ethereal solvents. Preferably, the ethereal solvent used is tetrahydrofuran. The reaction is preferably carried out at a temperature of from −20° C. and +20° C., more particularly from −10° C. and +10° C.
- This step provides the intermediates of general formula (3), the radicals of which are defined above.
- d. The fourth step entails converting the aromatic bromide of the intermediates of general formula (3) into phenylboronic acid of formula (I). This reaction, which is well documented in the literature (N. Miyaura & A. Suzuki, Chem. Rev., 1995, 95, 2457), is carried out in tetrahydrofuran at temperatures of from −78° C. and −20° C., preferably from −78° C. and −40° C. From 2 and 4 equivalents of a strong base are used such as butyllithium, preferably from 2.5 and 3.5 equivalents, and a trialkyl borate is used, such as trimethyl borate or triisopropyl borate. From 2 and 4 equivalents of the latter are used, preferably from 2.5 and 3.5 equivalents.
- According to another embodiment according to the invention, the synthesis of these novel phenylboronic acid derivatives of general formula (I) in which R4 is the radical of formula:
- is carried out in 4 steps starting from methyl 4-bromo-3-methylbenzoate (commercial product) according to the scheme of
FIG. 3 . - The first three steps are similar to the process described above.
- Therefore, the process for preparing compounds of general formula (I)
- in which R4 is the
- radical comprises the following steps, steps a) and b) not being implemented in the specific case in which R1 is a hydrogen atom:
- a) bromination in the benzylic position in the presence of a solvent, to give the compound (1):
- b) substitution of the bromine introduced in step a) in the benzylic position by an alkyl chain R5 containing 1 to 4 carbon atoms, to give the compound (2) as defined above:
- c) conversion of the ester function of the intermediates of general formula (2) or of methyl 4-bromo-3-methylbenzoate into a tertiary alcohol function, using at least two equivalents of an organomagnesium compound of formula R2-MgX
- wherein X is a chlorine or bromine atom
- and R2 is a methyl, ethyl, propyl, butyl or isobutyl radical to give the compound of general formula (3) as defined above:
- d) conversion of the aromatic bromide into aryl boronate in the presence of a solvent, a catalyst, a base and pinacolborane or pinacoldiborane, to give the compound of general formula (I).
- In greater detail, the steps of this process may be carried out as follows:
- a. The first step entails performing a bromination in the benzylic position to give the intermediate (1). This halogenation reaction is described in the literature. Various brominating agents may be used, such as, for example, bromine (K. Smith et al., J. Chem. Soc. Perkin. Trans., I, 2000, 2745), N-bromosuccinimide (P. Liu et al., Synthesis, 2001, 2078), sodium bromate (D. Kikuchi et al., J. Org. Chem., 1998, 6023) or else 1,3-dibromo-5,5-dimethylhydantoin (H. Jendralla et al., Liebigs Ann. Chem., 1995, 1253). This reaction is carried out most often in chlorinated solvents or in ethers. The brominating agent used with preference is N-bromosuccinimide at dichloromethane reflux. Preferably, benzoyl peroxide is also used, in a catalytic amount, as a free-radical reaction initiator. In order to activate the free-radical reaction the reaction mixture is irradiated with a 1000 watt lamp.
- This step provides the intermediate (1):
- b. The second step entails substituting the bromine introduced in
step 1 in the benzylic position by an alkyl chain R′1 containing 1 to 4 carbon atoms. In order to promote this substitution reaction the nucleophilic character of the alkyl group R′1 is increased by using an organometallic reagent R1-M in which M is a metal atom such as magnesium, copper or else zinc. This reaction is documented in the literature (B. H. Lipshutz and S. Sengupta, Organic Reactions, 1992, 41, 135). Preferably, copper in the form of copper iodide is employed in the presence of an organomagnesium compound R′1-MgX (X═Br, Cl, I) in order to generate an organocuprate. This reaction may be carried out in ethereal solvents. Preferably the ethereal solvent used is tetrahydrofuran. The reaction is carried out at low temperature, preferably from −40° C. and 0° C., more particularly from −40° C. and −20° C. - This step provides the intermediates of general formula (2), the radicals of which are defined above.
- c. The third step entails converting the ester function of the intermediates of general formula (2) or of methyl 4-bromo-3-methylbenzoate into a tertiary alcohol function, using at least two equivalents of an organomagnesium compound of formula R2-MgX, wherein X is a chlorine, bromine or iodine atom and R2 is an alkyl radical having 1 to 4 carbon atoms. This reaction is widely described in the literature. This reaction may be carried out in ethereal solvents. Preferably, the ethereal solvent used is tetrahydrofuran. The reaction is preferably carried out at a temperature of from −20° C. and +20° C., more particularly from −10° C. and +10° C.
- This step provides the intermediates of general formula (3), the radicals of which are defined above.
- d. In this fourth step, the aromatic bromide of the intermediates of general formula (3) may be converted into aryl boronate. This reaction, which is also well described in the literature (a/ M. Murata et al., J. Org. Chem., 1997, 62, 6458; b/ T. Ishiyama et al., J. Org. Chem., 1995, 60, 7508), is carried out in solvents such as DMF, tetrahydrofuran, DMSO or else dioxane. The reaction temperatures used are generally close to the reflux temperatures of the solvents. Generally, use is made of a palladium catalyst, preferably dichloro[1,1′-ferrocenylbis(diphenylphosphane)]palladium(II) dichloromethane or Pd(dppf)Cl2, a base, preferably potassium acetate or triethylamine, preferably from 2.5 and 3.5 equivalents, and a boron tetraalkoxide, preferably pinacolborane or pinacoldiborane. From 1 and 1.5 equivalents of the latter are used, preferably from 1.0 and 1.2 equivalents.
- The present invention likewise features the use of the disubstituted derivatives of phenylboronic acid of formula (I) and the compounds (1), (2) and (3) as synthesis intermediates for preparing vitamin D derivatives.
- Preferably, the compounds (I), (1), (2) and (3) according to the invention are used as intermediates in the synthesis of non-steroidal vitamin D derivatives displaying vitamin D activity.
- More preferably, the non-steroidal vitamin D derivatives are compounds of formula (IV):
- in which:
- R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
- R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
- R′1 is an alkyl radical having from 1 to 4 carbon atoms.
- In the preferred embodiment according to the invention, the compounds according to the invention are therefore employed in the synthesis according to the scheme indicated in
FIG. 4 . - According to the invention, the compounds of formula (IV) are preferably prepared from the compound (12) obtained according to the reaction scheme of
FIG. 4 . Compound (12) may be obtained from phenylboronic acid derivative compounds of general formula (I) according to the invention. A first reaction is a Suzuki coupling reaction from the derivatives of general formula (I) according to the invention and an aryl bromide of general formula (II). The Suzuki reaction product, of general formula (10), is fused with the benzyl bromide (11) in the presence of a base such as, for example, potassium carbonate, to give the compounds of general formula (12). Subsequently, a reaction is employed in accordance with methods which are well known to one skilled in the art—for example, and without limitation, such as described in WO 03/050067, which allow the compound (IV) to be obtained from the compound (12). - The present invention therefore features the process for preparing compounds of formula (IV) from phenylboronic acids of the present invention according to the following steps:
- a) A Suzuki coupling reaction from the compounds of general formula (I)
- in which:
- R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
- R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
- R4 is the —B(OH)2 radical or the radical of formula:
- and an aryl bromide of general formula (II):
- in which:
- R′1 is an alkyl radical having from 1 to 4 carbon atoms, to give the compound of general formula (10):
- in which:
- R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
- R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
- R′1 is an alkyl radical having from 1 to 4 carbon atoms;
- b) the Suzuki reaction product, of general formula (10), is fused with the benzyl bromide (11) in the presence of a base, such as potassium carbonate:
- c) liberation of the alcohol functions of the compound (11) to give the compound (IV).
- The present invention likewise features the compounds of formula (10), intermediates in the process defined above, of the following formula:
- in which:
- R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
- R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
- R′1 is an alkyl radical having from 1 to 4 carbon atoms; and their use in the synthesis of vitamin D analogues as described above and in
FIG. 2 . - In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative. In said examples to follow, all parts and percentages are given by weight, unless otherwise indicated.
-
- In a 6-liter reactor equipped with a condenser, a central mechanical stirrer and a thermometer, introduce 575 g (2.5 mol) of methyl 4-bromo-3-methylbenzoate, 3 liters of methylene chloride, 494 g (2.75 mol) of N-bromosuccinimide and 17 g of benzoyl peroxide (0.05 mol; 70% in water). Heat the mixture at reflux under irradiation with a 1000 watt lamp for 10 h. Wash the mixture twice with 1 liter of water, then with 1 liter of saturated sodium chloride solution. Evaporate the methylene chloride. Recrystallize the crude product obtained from heptane. This gives 596 g of methyl 4-bromo-3-bromomethylbenzoate in the form of off-white crystals (Yield=77%)
- Melting point: 100-101° C.
- 1H NMR (CDCl3; 400 MHz): 3.94 (s; 3H); 4.64 (s: 2H); 7.68 (d; 1H; Jo=8.3 Hz); 7.83 (d×d; 1H; Jo=8.3 Hz and Jm=2.0 Hz); 8.14 (d; 1H; Jm=2.0 Hz)
-
- In a 6-liter reactor equipped with a condenser, a central mechanical stirrer, a thermometer and a dropping funnel, introduce under nitrogen 141 g (0.46 mol) of methyl 4-bromo-3-bromomethylbenzoate, 4 liters of tetrahydrofuran and 8.9 g (0.045 mol) of copper(I) iodide. Cool the mixture to −40° C. using a bath of acetonitrile and dry ice. Add 168 cm3 of a 3M solution of ethylmagnesium bromide in diethyl ether and then allow the reaction temperature to increase to 0° C. After two hours of reaction hydrolyze the reaction mixture with 1 liter of 2.5M ammonium chloride solution. Separate the phases and extract the aqueous phase with 0.7 liter of methylene chloride. Combine the organic phases and evaporate the solvents. Pour heptane onto the product obtained and filter off the insoluble product which has formed. Evaporate the heptane and purify the resulting product by chromatography on silica gel (heptane/ethyl acetate=95/5). This gives 51 g of methyl 4-bromo-3-propylbenzoate in the form of colorless oil. (Yield=43%)
- 1H NMR (CDCl3; 400 MHz): 1.01 (t; 3H; J1=7.3 Hz); 1.68 (broad unresolved peak; 2H); 2.76 (t; 2H; J2=7.6 Hz); 3.92 (s; 3H); 7.61 (d; 1H; Jo=8.3 Hz); 7.71 (d×d; 1H; Jo=8.3 Hz and Jm=1.8 Hz); 7.89 (d; 1H; Jm=1.8 Hz)
-
- In a 1-liter three-necked round-bottomed flask, equipped with a magnetic stirrer, a thermometer and a dropping funnel, introduce under nitrogen 47 g (0.18 mol) of methyl 4-bromo-3-propylbenzoate in solution in 250 ml of tetrahydrofuran. Cool the mixture to −5° C. with the aid of a bath of ice and sodium chloride. Add 134 cm3 of a 3 M solution of ethylmagnesium bromide in diethyl ether, then allow the reaction temperature to increase without exceeding 5° C. After three hours of reaction, hydrolyze the reaction mixture with 170 cm3 of 2.5 M ammonium chloride solution. Extend the organic phase with 200 cm3 of ethyl acetate. Separate the phases and extract the aqueous phase with 2×200 cm3 of methylene chloride. Combine the organic phases, dry them over sodium sulfate and evaporate the solvents. This gives 49.8 g of 3-(4-bromo-3-propylphenyl)pentan-3-ol in the form of colorless oil. (Yield=96%)
- 1H NMR (CDCl3; 400 MHz): 0.77 (t; 6H; J2=7.4 Hz); 1.00 (t; 3H; J1=7.3 Hz); 1.68 (broad unresolved peak; 2H); 1.83 (broad unresolved peak; 4H); 2.73 (t; 2H; J2=7.7 Hz); 7.05 (d×d; 1H; Jo=8.3 Hz and Jm=2.2 Hz); 7.24 (d; 1H; Jm=2.2 Hz); 7.48 (d; 1H; Jo=8.3 Hz)
-
- In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-propylphenyl)pentan-3-ol (17.5 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 17.5 cm3 (43.7 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the reaction mixture for approximately 2 h with stirring at −70° C. and then add dropwise 10 cm3 of triisopropylborate (43.7 mmol), over 20 minutes. Leave the reaction mixture with stirring for 4 h, allowing the temperature to increase to −40° C. Hydrolyse the mixture with saturated NH4Cl solution and extract twice with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and evaporate the solvents under vacuum. This gives 5.4 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=3/1). This gives 1.92 g of 4-(1-ethyl-1-hydroxypropyl)-2-propylphenylboronic acid in the form of a highly viscous oil. (Yield=44%)
-
- In a 4-liter SVL reactor equipped with a magnetic stirrer, a thermometer and a dropping funnel, introduce under nitrogen 198.7 g (0.867 mol) of methyl 4-bromo-3-methylbenzoate in solution in 1 liter of tetrahydrofuran. Cool the mixture to −5° C. with the aid of a bath of ice and sodium chloride. Add 636 cm3 of a 3M solution of ethylmagnesium bromide in diethyl ether, then allow the reaction temperature to increase to ambient temperature. After four hours of reaction, hydrolyze the reaction mixture with 2 liters of a 1N hydrochloric acid solution. After decanting and separation, extract the aqueous phase with 0.5 liter of ethyl acetate. Wash the combined organic phases with 0.4 liter of water (3×). After drying over sodium sulfate, the product obtained after evaporation of the solvents is purified by chromatography on silica gel (heptane/ethyl acetate=95/5). This gives 150.2 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol in the form of a colorless oil (Yield=67%)
- 1H NMR (CDCl3; 400 MHz): 0.79 (t; 6H; J2=7.4 Hz); 1.63 (s; 1H); 1.83 (broad unresolved peak; 4H); 2.42 (s; 3H); 7.05 (d×d; 1H; Jo=8.3 Hz and Jm=2.2 Hz); 7.27 (d; 1H; Jm=2.2 Hz); 7.48 (d; 1H; Jo=8.3 Hz)
-
- In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol (19.4 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 23.3 cm3 (58 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the mixture for approximately 2 h with stirring at −70° C. and then add dropwise 13.5 cm3 of triisopropyl borate (58 mmol), over 20 minutes. Leave the mixture with stirring for 3 h, allowing the temperature to increase to −10° C. Hydrolyse the mixture with saturated NH4Cl solution and extract two times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and dry them over sodium sulfate. Evaporate the solvents under vacuum. This gives 5 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=9/1) to give 4-(1-ethyl-1-hydroxypropyl)-2-methylphenylboronic acid in the form of a highly viscous oil. (Yield=71%)
- 1H NMR (CDCl3; 400 MHz): 0.78 (t; 3H; J2=7.4 Hz); 1.86 (broad unresolved peak; 4H); 2.86 (s; 3H); 7.31 (m; 3H); 8.22 (d; 1H; Jo=8.3 Hz)
-
- In a three-necked flask, introduce under nitrogen 2 g of 3-(4-bromo-3-propylphenyl)pentan-3-ol (7 mmol) and 20 cm3 of N,N-dimethylformamide. Add 2.06 g (21 mmol) of potassium acetate and 1.87 g (7.3 mmol) of bis(pinacol)diborane. Add 0.229 g (0.28 mmol) of dichloro[1.1′-ferrocenylbis(diphenylphosphane)]palladium(II) dichloromethane [Pd(dppf)Cl2] and heat the reaction mixture at reflux for 2 h 30 min. Hydrolyse the mixture and extract it twice with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and evaporate the solvents under vacuum. This gives 3.6 g, which is chromatographed on silica gel (heptane/ethyl acetate=8/2). This gives 1.55 g of 3-[3-propyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentan-3-ol in the form of a highly viscous oil. (Yield=76%)
- 1H NMR (CDCl3; 400 MHz): 0.76 (t; 6H; J2=7.4 Hz); 0.95 (t; 3H; J1=7.3 Hz); 1.36 (s; 12H); 1.60 (broad unresolved peak; 2H); 1.67 (s; 1H); 1.84 (broad unresolved peak; 4H); 2.88 (t; 2H; J2=7.6 Hz); 7.18 (m; 2H); 7.75 (d; 1H; Jo=8.4 Hz)
- Each patent, patent application, publication, text and literature article/report cited or indicated herein is hereby expressly incorporated by reference.
- While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.
Claims (3)
1. A non-steroidal vitamin D analogue prepared from a disubstituted phenylboronic acid compound of the following structural formula (I):
in which:
R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
R4 is the —B(OH)2 radical or the radical of formula:
2. The non-steroidal vitamin D analogue as defined by claim 1 , having the structural formula (IV):
in which:
R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
R′1 is an alkyl radical having from 1 to 4 carbon atoms.
3. A process for the preparation of a non-steroidal vitamin D analogue as defined by claim 2 , comprising:
a) Suzuki coupling a compound having the formula (I):
in which:
R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and
R4 is the —B(OH)2 radical or the radical of formula:
and an aryl bromide having the formula (II):
in which:
R′1 is an alkyl radical having from 1 to 4 carbon atoms, to obtain a compound of formula (10):
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US12/635,255 US20100145105A1 (en) | 2003-12-18 | 2009-12-10 | Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof |
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FR03/14946 | 2003-12-18 | ||
FR0314946A FR2864083B1 (en) | 2003-12-18 | 2003-12-18 | NOVEL PHENYL BORONIC ACID DERIVATIVES AND METHODS FOR THEIR PREPARATION |
PCT/FR2004/003192 WO2005061520A1 (en) | 2003-12-18 | 2004-12-10 | Novel phenyl-boronic acid derivatives and methods for the preparation thereof |
US11/454,859 US7659421B2 (en) | 2003-12-18 | 2006-06-19 | Phenylboronic acid compounds and intermediates and processes for the preparation thereof |
US12/635,255 US20100145105A1 (en) | 2003-12-18 | 2009-12-10 | Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof |
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US12/635,255 Abandoned US20100145105A1 (en) | 2003-12-18 | 2009-12-10 | Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof |
US12/635,299 Abandoned US20100087669A1 (en) | 2003-12-18 | 2009-12-10 | Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof |
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AT (1) | ATE421969T1 (en) |
CA (1) | CA2545736A1 (en) |
CY (1) | CY1109026T1 (en) |
DE (1) | DE602004019309D1 (en) |
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ES (1) | ES2320349T3 (en) |
FR (1) | FR2864083B1 (en) |
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PT (1) | PT1768988E (en) |
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FR2878245B1 (en) * | 2004-11-19 | 2007-02-16 | Galderma Res & Dev | NOVEL PROCESS FOR THE PREPARATION OF 3- (5 '- (3,4-BIS-HYDROXYMETHYL-BENZYLOXY) -2'-ETHYL-2-PROPYL-BIPHENYL-4-YL) - PENTA-3OL |
EP2406233B1 (en) | 2009-03-09 | 2013-11-13 | Bristol-Myers Squibb Company | Aza pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists |
DK2755980T3 (en) * | 2011-09-14 | 2020-01-27 | Dow Agrosciences Llc | PROCEDURES AND SYSTEMS FOR CREATING BORONIC ACID AND ITS INTERMEDIATES |
JP6164230B2 (en) * | 2014-12-26 | 2017-07-19 | 横浜ゴム株式会社 | Tire condition monitoring system |
US10548908B2 (en) | 2016-09-15 | 2020-02-04 | Nostopharma, LLC | Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification |
Citations (3)
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US20020143024A1 (en) * | 1998-07-06 | 2002-10-03 | Natesan Murugesan | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
US20080019915A1 (en) * | 2005-11-08 | 2008-01-24 | Sara Hadida-Ruah | Modulators of ATP-binding cassette transporters |
US7888356B2 (en) * | 2002-12-18 | 2011-02-15 | Anacor Pharmaceuticals, Inc. | Antibiotics containing borinic acid complexes and methods of use |
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2004
- 2004-12-10 ES ES04805689T patent/ES2320349T3/en active Active
- 2004-12-10 WO PCT/FR2004/003192 patent/WO2005061520A1/en not_active Application Discontinuation
- 2004-12-10 PT PT04805689T patent/PT1768988E/en unknown
- 2004-12-10 DE DE602004019309T patent/DE602004019309D1/en active Active
- 2004-12-10 CA CA002545736A patent/CA2545736A1/en not_active Abandoned
- 2004-12-10 SI SI200431022T patent/SI1768988T1/en unknown
- 2004-12-10 PL PL04805689T patent/PL1768988T3/en unknown
- 2004-12-10 AT AT04805689T patent/ATE421969T1/en active
- 2004-12-10 DK DK04805689T patent/DK1768988T3/en active
- 2004-12-10 EP EP04805689A patent/EP1768988B1/en not_active Not-in-force
- 2004-12-17 AR ARP040104720A patent/AR046946A1/en unknown
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020143024A1 (en) * | 1998-07-06 | 2002-10-03 | Natesan Murugesan | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
US7888356B2 (en) * | 2002-12-18 | 2011-02-15 | Anacor Pharmaceuticals, Inc. | Antibiotics containing borinic acid complexes and methods of use |
US20080019915A1 (en) * | 2005-11-08 | 2008-01-24 | Sara Hadida-Ruah | Modulators of ATP-binding cassette transporters |
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ES2320349T3 (en) | 2009-05-21 |
DK1768988T3 (en) | 2009-04-20 |
WO2005061520A1 (en) | 2005-07-07 |
CA2545736A1 (en) | 2005-07-07 |
EP1768988A1 (en) | 2007-04-04 |
CY1109026T1 (en) | 2014-07-02 |
ATE421969T1 (en) | 2009-02-15 |
AR046946A1 (en) | 2006-01-04 |
US20100087669A1 (en) | 2010-04-08 |
FR2864083A1 (en) | 2005-06-24 |
PL1768988T3 (en) | 2009-07-31 |
FR2864083B1 (en) | 2007-04-13 |
EP1768988B1 (en) | 2009-01-28 |
DE602004019309D1 (en) | 2009-03-19 |
US20070015931A1 (en) | 2007-01-18 |
SI1768988T1 (en) | 2009-06-30 |
PT1768988E (en) | 2009-04-23 |
US7659421B2 (en) | 2010-02-09 |
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