[go: up one dir, main page]

WO2008140328A2 - Nouveaux intermédiaires, leur procédé de préparation et synthèse de 1,4-benzoquinones - Google Patents

Nouveaux intermédiaires, leur procédé de préparation et synthèse de 1,4-benzoquinones Download PDF

Info

Publication number
WO2008140328A2
WO2008140328A2 PCT/NO2008/000172 NO2008000172W WO2008140328A2 WO 2008140328 A2 WO2008140328 A2 WO 2008140328A2 NO 2008000172 W NO2008000172 W NO 2008000172W WO 2008140328 A2 WO2008140328 A2 WO 2008140328A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
accordance
halogen
benzyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/NO2008/000172
Other languages
English (en)
Other versions
WO2008140328A3 (fr
Inventor
Hans-René BJORSVIK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vestlandets Innovasjonsselskap AS
Original Assignee
Bergen Teknologioverforing AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/798,749 external-priority patent/US7528271B2/en
Priority claimed from NO20072520A external-priority patent/NO20072520L/no
Application filed by Bergen Teknologioverforing AS filed Critical Bergen Teknologioverforing AS
Publication of WO2008140328A2 publication Critical patent/WO2008140328A2/fr
Publication of WO2008140328A3 publication Critical patent/WO2008140328A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures

Definitions

  • the present invention relates to a process for the preparation of 1 ,4-benzoquiones, and novel compounds and intermediates.
  • the present invention also relates to a method for the preparation of coenzyme Q n , preferable the coenzyme Q 10 , and a method for continuous synthesis of 1 ,4-benzoquiones
  • the present invention relates to a new efficient synthesis of 2,3-dimethoxy- 5-methyl-[l,4]benzoquinone, also known as coenzyme Qo (CoQ 0 ).
  • This methodology is being successfully incorporated into the synthesis of higher order ubiquinones, such as coenzyme
  • CoQ n , n ⁇ 12 isoprene units are found in the mitochondria of every cell of nearly all types of vertebrates.
  • the Coenzyme Q n constitutes one of the more important classes of compounds
  • CoQ 10 is an important antioxidant use by the cells to trap free radicals. Studies have shown that CoQ 10 can exert efficacy in treating patients with mitochondrial disorders, and for the treatment of neurodegenerative diseases such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
  • Patent 4,952,712, 1990. and in some cases toxic by-products are formed.
  • Matsumoto, M.; Kobayashi, H. J. Org. Chem. 1985, 50, 1766 In the synthesis of the simplest ubiquinone, CoQo (formula I), oxidation of 3,4,5-trimethoxytoluene with various reagents, including Fremy's salt, ceric(IV)ammonium nitrate, H 2 O 2 in HCO 2 H, weta-chloroperbenzoic acid or H 2 O 2 in AcOH, and H 2 SO 4 , give 2,3-dimethoxy-5-methyl-[l,4]benzoquinone in only low yields.
  • a first object of the present invention is to obtain a process for the preparation of 1,4- benzoquiones of formula (II)
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, branched or unbranched Ci-C 6 alkyl, phenyl and benzyl, wherein phenyl and benzyl is optionally substituted by one or more substituent independently selected from the group consisting of Ci-C 6 alkyl and halogen, and wherein Ci-C 6 alkyl is optionally substituted with one or more halogen susbstituents, and wherein R and R together can form a Ci-C 6 -alkylene radical, optionally substituted by one or more susbstituents independently selected from the group comprising Ci-C 6 alkyl, benzyl, phenyl and halogen, by reacting a compound of formula (III)
  • R 1 , R 2 , R 3 and R 4 are as defined above, with a peroxide oxidant preferable H 2 O 2 , under acidic conditions, preferable in AcOH, with the presence of an acid catalyst such as para-toluenesulfonic acid.
  • a preferred objective of this aspect is to provide a process for the preparation of 2,3- dimethoxy-5-methyl-[l,4]benzoquinone, also known as coenzyme Q 0 (CoQ 0 ), i.e. where R entities of the formula (III) are defined as follows; R 1 is methyl, R 2 and R 3 is methoxy, and R 4 is H. This preferred embodiment is starting from 3,4,5-trimethoxytoluene.
  • peroxide oxidizing agents can be used according to the process of the present invention, and the peroxide is preferable selected from the group comprising tert- butylhydrperoxide, cumene hydroperoxide, and hydrogen peroxide, preferable H 2 O 2 .
  • Various acidic solvents can be used in the process according to the present invention, and the solvent is preferable selected from the group comprising formic acid, acetic acid, propionic acid, preferable AcOH.
  • Br ⁇ ndsted acids can be used as acid catalyst in the process according to the invention, and the Br ⁇ ndsted acid is preferable selected from the group comprising sulphuric acid, nitric acid, phosphoric acid, and para-toluensulphonic acid (p-TSA), preferable p-TS A.
  • p-TSA para-toluensulphonic acid
  • An preferred embodiment of process according to the invention further contains the steps of i) cooling the reaction mixture to 0-5°C, preferable over a period of about 10 minutes, and ii) adding HNO 3 in order to increase the yield of formula (II).
  • a further aspect of the present invention relates to novel intermediates of formula (IV),
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, branched or unbranched CpC 6 alkyl, phenyl and benzyl, wherein phenyl and benzyl is optionally substituted by one or more substituent independently selected from the group consisting of Ci-C 6 alkyl and halogen, and wherein Ci-C 6 alkyl is optionally substituted with one or more halogen susbstituents, and wherein R 2 and R 3 together can form a d-C 6 -alkylene radical, optionally substituted by one or more susbstituents independently selected from the group comprising C 1 -C 6 alkyl, benzyl, phenyl and halogen.
  • a preferred embodiment of this aspect relates to a compound of formula (IV), wherein R 1 is methyl, R 2 and R 3 are methoxy, and R 4 is H or a halogen.
  • a further preferred embodiment of this aspect relates to a compound of formula (IV), wherein R 1 is methyl, R 2 and R 3 are methoxy, and R 4 is H.
  • a further aspect of the invention relates to novel compounds of the formula (V)
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, branched or unbranched C 1 -C 6 alkyl, phenyl and benzyl, wherein phenyl and benzyl is optionally substituted by one or more substituent independently selected from the group consisting of Ci-C 6 alkyl and halogen, and wherein Ci-C 6 alkyl is optionally substituted with one or more halogen substituents, and wherein R and R together can form a Ci-C 6 -alkylene radical, optionally substituted by one or more substituents independently selected from the group comprising C 1 -C 6 alkyl, benzyl, phenyl and halogen.
  • a preferred embodiment of this aspect relates to a compound of formula (V), wherein R 1 is methyl, R 2 and R 3 are methoxy, and R 4 is H or a halogen.
  • a further preferred embodiment of this aspect relates to a compound of formula (V), wherein R 1 is methyl, R 2 and R 3 are methoxy, and R 4 is H.
  • a further aspect of the invention relates to novel compounds of the formula (VI)
  • R and R are independently selected from the group consisting of H, branched or unbranched C 1 -C 6 alkyl, phenyl and benzyl, wherein phenyl and benzyl is optionally substituted by one or more substituent independently selected from the group consisting of C 1 -C 6 alkyl and halogen, and wherein C 1 -C 6 alkyl is optionally substituted with one or more halogen substituents, and wherein R 2 and R 3 together can form a Q-C ⁇ -alkylene radical, optionally substituted by one or more substituents independently selected from the group comprising C 1 -C 6 alkyl, benzyl, phenyl and halogen.
  • a further preferred embodiment of this aspect relates to a compound of formula (VI), wherein R 2 and R 3 are methoxy.
  • a further aspect of the present invention relates to a process for the synthesis of higher order ubiquinones, i.e. for the preparation of coenzyme Q n of formula (VII)
  • R 1 , R 2 , R 3 and R 4 are as defined above, with a peroxide oxidant preferable H 2 O 2 , in an acidic solvent, preferable AcOH, with the presence of an acid catalyst such as para- toluenesulfonic acid, and then activating the compound of formula (II) by conventional methods, and coupling of the activated compound of formula (II) with a compound of formula (VIII)
  • a further aspect of the present invention relates to a method for continuous synthesis of 1,4- benzoquiones , wherein the synthesis takes place in a reactor that encompasses an annular reaction room for supply and outflow of reactants, and where the reactants are fed from one end of the annular reaction room to the other, and thereby are forced through perforations in a number of discs arranged on an oscillator set up so that good mixing is obtained, and where the ratio between "the area of the internal surface of the reaction room” and "the volume of the annular reaction room” is in the area 5-20 cm /cm 3 , preferably about 10 cm 2 /cm , and wherein said 1 ,4-benzoquiones with the formula (II)
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, branched or unbranched C 1 -C 6 alkyl, phenyl and benzyl, wherein phenyl and benzyl is optionally substituted by one or more substituent independently selected from the group consisting Of C 1 -C 6 alkyl and halogen, and wherein Ci-C 6 alkyl is optionally substituted with one or more halogen substituents, and wherein R and R together can form a Ci-C 6 -alkylene radical, optionally substituted by one or more substituents independently selected from the group comprising Ci-C 6 alkyl, benzyl, phenyl and halogen, is prepared by reacting a compound of formula (III)
  • R 1 , R 2 , R 3 and R 4 are as defined above, with a peroxide oxidant preferable H 2 O 2 , in an acidic solvent, preferable AcOH, with the presence of an acid catalyst such as para- toluenesulfonic acid.
  • Ci to C 6 alkyl represents a straight- or branched-chain saturated hydrocarbon containing 1 to 6 carbon atoms which may be unsubstituted or substituted by one or more substituents.
  • Examples of Cj to Ci 2 alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, wo-butyl, tert-butyl, pentyl, and the like.
  • phenyl as used herein, mean a -C 6 H 5 group.
  • benzyl as used herein, means a -CH 2 C 6 H 5 group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • 172.13, 0.01 mol are dissolved in glacial acetic acid to give a total volume of 50 ml and the solution is connected to the pump 1.
  • the hydrogen peroxide (0.2 mol, MW 34.02, 21.6 ml if H 2 O 2 at 30% and 17.5 ml if H 2 O 2 at 35%) diluted to 50 ml with glacial acetic acid is connected to the pump 2.
  • the nitric acid (90%, 0.05 mol, MW 63.02, d 1.49, 3.15 g, 3.5 g solution 90%, 2.35 ml solution 90%) dissolved in acetic acid (to 50 ml) is connected to the pump 3.
  • Example 6 Example 5 - Continuous synthesis of 2,3-Dimethoxy-5-methyl- [ 1 ,41benzoquinone TCoQnI .
  • the nitric acid (90%, 0.05 mol, MW 63.02, d 1.49, 3.15 g, 3.5 g solution 90%, 2.35 ml solution 90%) dissolved in acetic acid (to 50 ml) is connected to the pump 2.
  • the pump 1 is pumping approximately 3.8 ml/min for each of the two reagent solutions (total speed flow 7.6 ml/min, i.e. 38 ml reactor volume/5 min RT).
  • Isoversinic tubes (ID 2 mm) was used on the peristaltic pump.
  • the residence time of the reaction was about 5 min (38 ml volume reactor) and the reaction was performed at 75°C pumping the solutions of the pumps 1.
  • the nitric acid solution was pumped at 3.8 ml/min into the second section of the reactor (11 ml, volume reactor) cooled by a cold water circuit. About 50 ml of glacial acetic acid was also pumped in the reactor at the end in order to push out all of the reaction solution.
  • FIG. 1 shows a drawing of an embodiment example of a reactor
  • figure 2 shows a longitudinal section of a variant of a reactor.
  • Figure 1 shows a reactor 20 that is composed of several part components, where at least some of the components can be joined together with the help of one or more fastening connections, such as for example, a clamp connection 29.
  • the different part components, or sections encompass correspondingly shaped jointing parts so that the reactor can be put together with as many sections as is desirable.
  • a motor 28 or the like is arranged in the reactor adjoining the oscillator 26, where the oscillator 26, in connection with the motor 28, forces, in relation to at least one reactor chamber 22 in the reactor, a pulsating forward and backward movement of the oscillator 26.
  • the motor 28 preferably has a speed regulator and the motor 28 is controlled so that the oscillator 26 pulsates at a predetermined and controllable amplitude and frequency.
  • the reactor can also comprise a lower support foot 21, and also an upper product outlet pipe 54.
  • the reactor 20 comprises externally a number of communication openings 64, 82 in the form of inlets and outlets for supply of reactants and outflow of products, respectively. The different fluids are fed into the reactor via the inlets and pumped through the reactor until they finally are led out through the outlets arranged preferably in the upper section of the reactor at the product outlet pipe 54.
  • the reactor can have a length in the area 5-300 cm, more preferably 50-200 cm, most preferably 80-150 cm, and the flow of fluid through the reactor can be 0.1-1000 ml/min.
  • a number of controlled pumps (not shown in detail in the figures), different fluids are fed into the reactor 20.
  • the reactor 20 can be of any shape imaginable, but a preferred embodiment of the reactor has a cylindrical shape as shown in the figures.
  • the diameter and length of the reactor can also be varied.
  • One or more chemical compounds/reactants can be dissolved in separate solvents, or there can be one or several compounds in liquid phase, and the different fluids can be fed into the reactor with different fluid flow velocities controlled by the different pumps.
  • the reactor can function in any position, but it is generally preferred that the reactor is arranged vertically, and that the different fluids are fed into the bottom section of the reactor, and that they are thus pumped against gravitational forces through the reactor, and that intermediate products or final products are led out at a higher level in the reactor.
  • the oscillator 26 is preferably shaped as a rod or strut comprising a number of ring-formed, external discs 30 arranged mutually spaced apart in the longitudinal direction of the oscillator, where the oscillator with the discs is inserted with a close fit in at least one chamber 22 of the reactor so that an annular reaction room 24 for conversion of chemical reactants is formed in the reactor, between the outer surface of the oscillator 26 and the internal surface 22 of the chamber.
  • Said ring-formed discs 30 are fitted with a number of perforations 30a to permit through flow of fluid, and to contribute to the mixing of fluid in the chamber 22.
  • the number of discs 30 in the reactor 20, and the number of perforations 30a, and the diameter of the perforations 30a will be decided according to the reaction that is carried out in the reactor 20. Typically, one will prefer a large number of discs, and also many small perforations.
  • the discs 30 can have a mutual centre-to-centre distance in the area 0.2 cm - 3.0 cm, more preferably in the area 0.8-1.4 cm, and most preferably about 1 cm.
  • Each disc 30 can be fitted with 1-10 perforations 30a, preferably 2-6 perforations, more preferably 3-5 perforations, and most preferably 4 perforations.
  • each perforation 30a can have a diameter in the area 0.2-3 mm, more preferably in the area 0.5-2 mm, and most preferably about 1.25 mm.
  • the ratio between the area of the internal surface of the chamber 22 and the volume of the annular reaction room 24 can, for example, be in the area 1.5-35 cm 2 /cm 3 .
  • the ratio between the area of the internal surface of the chamber 22 and the volume of the annular reaction room 24 can be more specifically in the area 5-20 cm 2 /cm 3 .
  • the ratio between the area of the internal surface of the chamber 22 and the volume of the annular reaction room 24 can be about 10 cm 2 /cm 3 .
  • the reactor according to the present invention provides such a ratio between the heating/cooling surface and reaction volume that has not been previously available.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé pour la préparation de 1,4-benzoquinones représentées par la formule (II) dans laquelle R1, R2, R3 et R4 sont indépendamment choisis dans le groupe constitué par H, un alkyle en C1-C6 ramifié ou non ramifié, un phényle et un benzyle, où le phényle et le benzyle sont facultativement substitués par un ou plusieurs substituants indépendamment choisis dans le groupe constitué par alkyle en C1-C6 et halogène et où l'alkyle en C1-C6 est facultativement substitué par un ou plusieurs substituants halogène, et dans laquelle R2 et R3 peuvent ensemble former un radical d'alkylène en C1-C6, facultativement substitué par un ou plusieurs substituants indépendamment choisis dans le groupe constitué par alkyle en C1-C6, benzyle, phényle et halogène. Un composé préféré est la 2,3- diméthoxy-5-méthyl-[l,4]benzoquinone, également connue en tant que coenzyme Q0 (CoQ0). L'invention concerne également de nouveaux composés et de nouveaux intermédiaires, et un procédé pour la préparation de la coenzyme Qn, de préférence la coenzyme Q10. L'invention concerne également un procédé pour la synthèse continue de 1,4- benzoquinones dans un réacteur à écoulement continu.
PCT/NO2008/000172 2007-05-16 2008-05-16 Nouveaux intermédiaires, leur procédé de préparation et synthèse de 1,4-benzoquinones Ceased WO2008140328A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
NO20072520 2007-05-16
US11/798,749 US7528271B2 (en) 2007-05-16 2007-05-16 Intermediates, process for their preparation and synthesis of 1,4-benzoquiones
US11/798.749 2007-05-16
NO20072520A NO20072520L (no) 2007-05-16 2007-05-16 Novel intermediates, process for their preparation and synthesis of 1,4-benzoquinones

Publications (2)

Publication Number Publication Date
WO2008140328A2 true WO2008140328A2 (fr) 2008-11-20
WO2008140328A3 WO2008140328A3 (fr) 2009-01-29

Family

ID=39745036

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NO2008/000172 Ceased WO2008140328A2 (fr) 2007-05-16 2008-05-16 Nouveaux intermédiaires, leur procédé de préparation et synthèse de 1,4-benzoquinones

Country Status (1)

Country Link
WO (1) WO2008140328A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2010649A1 (fr) * 1968-06-11 1970-02-20 Takeda Chemical Industries Ltd

Also Published As

Publication number Publication date
WO2008140328A3 (fr) 2009-01-29

Similar Documents

Publication Publication Date Title
US7179928B2 (en) Synthesis of triphenylphosphonium quinols and quinones
EP1467958B1 (fr) Procede de preparation de 3,3',5,5',6,6'-hexaalkyl-2,2'-biphenols, de 3,3',4,4',5,5'-hexaalkyl-2,2'-biphenols et de 3,3',4,4',5,5',6,6'-octaalkyl-2,2'-biphenols
JPH10279506A (ja) ビスヒドロキシメチル化合物の製造方法
CN110002961B (zh) 一种去外消旋化合成手性醇的方法
JP2008169324A (ja) １，２，３，４−テトラヒドロアントラセン−９，１０−（メタ）アクリレート化合物およびその製造方法
EP3728167B1 (fr) Procédé de préparation de crisaborole
US7528271B2 (en) Intermediates, process for their preparation and synthesis of 1,4-benzoquiones
CN105693569A (zh) 3-[4-(甲基磺酰基)-2-氯苯甲酰基]二环[3.2.1]-2,4-辛二酮的合成方法
CN112250567B (zh) 一种AMG837及手性γ-甲基苯戊醇的合成方法
García-Lacuna et al. Synthesis of treprostinil: key Claisen rearrangement and catalytic Pauson–Khand reactions in continuous flow
WO2008140328A2 (fr) Nouveaux intermédiaires, leur procédé de préparation et synthèse de 1,4-benzoquinones
CN109776295B (zh) 一种邻位含二氟亚甲基的芳基碘化合物及制备方法
CN115232163A (zh) 一种硅中心手性分子化合物及其制备方法与应用
EA005857B1 (ru) Промежуточные соединения для использования при получении витамина e
JP3128703B2 (ja) 発色性化合物の製造方法及びその中間体類並びにそれらの製造方法
CN107324976B (zh) 一种制备(E)-β-烷基苯乙烯类化合物的方法
EP0663394B1 (fr) Procédé pour la préparation de 5-amino-dihydropyrrole, produit intermédiaire et procédé pour la préparation du produit intermédiaire
EP0331422A2 (fr) Procédé pour la préparation de 2-acylrésorcinoles
EP0561664A1 (fr) Procédé de préparation de 4-pyrimidinones
WO2023073080A1 (fr) Procédé de préparation de dérivés d'acyle
JP2000063321A (ja) 光学純度の高い長鎖β−ヒドロキシカルボン酸の製造方法
JPS61212538A (ja) α−アリ−ルアルカン酸エステル類の製造法
CN117986106A (zh) 一种3-溴-螺[5,5]三烯酮类化合物的制备方法以及应用
KR100570279B1 (ko) 코엔자임 Ｑｎ의 중간체 및 그 중간체의 제조방법
CN116813456A (zh) 由苄位亚甲基类化合物合成环羰基类化合物的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08766891

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08766891

Country of ref document: EP

Kind code of ref document: A2