EP3655391A1 - Procédé de production de 3,7-diméthyl-9-(2,6,6-triméthyl-1-cyclohexèn-1-yl)-nona-2z,7e-dien-4-yne-1,6-diol - Google Patents

Procédé de production de 3,7-diméthyl-9-(2,6,6-triméthyl-1-cyclohexèn-1-yl)-nona-2z,7e-dien-4-yne-1,6-diol

Info

Publication number
EP3655391A1
EP3655391A1 EP18743479.0A EP18743479A EP3655391A1 EP 3655391 A1 EP3655391 A1 EP 3655391A1 EP 18743479 A EP18743479 A EP 18743479A EP 3655391 A1 EP3655391 A1 EP 3655391A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
reaction
added
reaction mixture
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.)
Pending
Application number
EP18743479.0A
Other languages
German (de)
English (en)
Inventor
Werner Bonrath
Rolf Kuenzi
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.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
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
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of EP3655391A1 publication Critical patent/EP3655391A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/10—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by etherified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to an improved method for producing 3,7-dimethyl- 9-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-nona-2Z,7E-dien-4-yne-1 ,6-diol.
  • vitamin A is an intermediate in a process to produce vitamin A (and its derivatives as i.e. vitamin A acetate).
  • Oxenine as an intermediate in the production of vitamin A is known for a long time. It is known i.e. from Isler et al., Helv. Chim. Acta 30, 191 1 (1947); from US 2451739 or from US 3046310.
  • Vitamin A (fl//-£)-retinol (vitamin A) is an important ingredient for many applications. Vitamin A (and its derivatives) plays a role in a variety of functions throughout the (human and animal) body, such as e.g. vision process, gene transcription, immune function, bone metabolism, haematopoiesis, skin and cellular health and antioxidant function.
  • vitamin A acetate which is the compound of the following formula ( ⁇ ):
  • Vitamin A (retinol or its derivatives) can be produced (when starting from oxenine, which is the compound of formula (I)) according to the following reaction schemes, which are known i.e. from US2451739: ⁇
  • Oxenine is usually obtained by the condensation reaction of the following compound of formula (III) and (IV)
  • This condensation reaction is usually carried out as a Grignard reaction, wherein a compound of formula (III)
  • step (a) the compound of formula (IV), which is (Z)-l -pentol (or (Z)-3-methylpent-2-en-4- yn-1 -ol):
  • Ri is a Ci-C alkyl group
  • R 2 is a C3-C-6 alkylene group
  • step (b) the reaction product of step (a) is reacted with a compound of formula (XI)
  • X is CI, Br, or I (preferably Br), and
  • step (c) the reaction product of step (b) is reacted with a compound of formula (III)
  • step (b) and in step (c) the reactions are carried out in 2-methyltetrahydrofuran (also known as 2-methyloxolane) as a solvent.
  • 2-methyltetrahydrofuran also known as 2-methyloxolane
  • the present invention relates to a process (P) to produce a compound of formula (I)
  • Ri is a Ci-C alkyl group
  • R2 is a C3-C-6 alkylene group
  • step (a) the reaction product of step (a) is reacted
  • X is CI, Br, or I (preferably Br), and
  • step (c) the reaction product of step (b) reacted with a compound of formula (III)
  • step (b) and of step (c) are carried out in 2-methyltetrahydrofuran as solvent.
  • the present invention relates to a process ( ⁇ '), which is process (P), wherein no alkali metal is used in any process steps of the process according to the invention.
  • step (a) the compound of formula (IV),
  • Ri is a Ci-C alkyl group
  • R 2 is a C3-C-6 alkylene group
  • a preferred embodiment of the present invention is a process, wherein Ri is -CH 3 or -CH 2 CH 3 and R 2 is C 3 -C 5 alkylene group.
  • a more preferred embodiment of the present invention is a process, wherein the compound of formula (X) is a compound of formula ( ⁇ '), (X") or (X'")
  • the two starting materials can be added in equimolar ratios.
  • step (a) is usually (and preferably) catalyzed by at least one acid.
  • the acid can be any commonly used acid.
  • Very preferred acids are i.e. sulfuric acid, p-toluene sulfonic acid hydrate (pTsOH) or benzoic acid.
  • the acid is used in a catalytic amount. Usually in an amount which is about 0.001 - 0.0000 1 mol equivalent (in regard to compound of formula (IV)).
  • an ion exchanger instead of using at least one acid, it is also possible to use an ion exchanger to catalyse the reaction. Strongly acidic cation exchange resins are usually used. Such acidic cation exchangers are available commercially.
  • Suitable ion exchangers are i.e. Amberlyst 15 ® , Amberlyst 36 ® , Amberlyst 70 ® and Dowex 50 WX12 ® .
  • a base is added at the end of the reaction to stop. Any commonly known base (or a mixture of bases) can be used.
  • step (a) is exothermic. Therefore, the reaction mixture is usually cooled. This is done by any usually used external cooling systems.
  • step (a) can be carried out without any solvent.
  • the reaction of step (a) can be carried out with at least one solvent.
  • Suitable solvents are polar aprotic solvents such as ethers.
  • step (b) the reaction product of step (a) is reacted with a compound of formula compound of formula (XI)
  • X is CI, Br, or I (preferably Br).
  • the compound of formula (XI) is a classical Grignard compound. This compound is usually produced in situ by the addition of magnesium and bromoethane. This is the common way of preparing this compound.
  • the reaction condition for preparing the compound of formula (XI) are the commonly used ones.
  • step (a) The reaction product of step (a) is added slowly to the reaction solution in which the compound of formula (XI) was produced.
  • step (b) 2-Methyltetrahydrofuran is used in step (b) as a solvent.
  • step (b) is usually carried out at elevated temperature. Usually at a temperature which is between 30 - 50°C.
  • step (c) the compound of formula (III),
  • step (c) is usually carried out at elevated temperature. Usually above 30°C up to about 40°C.
  • An essential feature of the new and improved process of the present invention is that the reactions of steps (b and c) is carried out in 2-methyltetrahydrofuran as solvent.
  • reaction mixture is poured into an ice/water solution and then this solution is acidified.
  • Triethylamine 99.8 %, 0.096 mMol
  • the non-reacted starting material was removed under reduced pressure (about 27 °C and up to 30 mbar).
  • reaction product ((Z)-1 -pentol/isopropenylmethyl ether -product) was dissolved into 8 ml of 2-methyltetrahydrofuran (water-free).
  • step (b)) the (Z)-1 -pentol/isopropenylmethyl ether-product, which was obtained in the first step was added dropwise to the Grignard solution.
  • the temperature of the reaction mixture was kept at a temperature range between 35 - 40 °C.
  • the reaction mixture was stirred at that temperature for about an hour.
  • the reaction temperature was kept at a temperature of between 35 - 40 °C.
  • the reaction mixture was stirred at a temperature of between 35 - 40 °C for about an hour, cooled to room temperature (20 - 25°C), and added to 67g of a water/ice mixture under stirring.
  • the mixture was stirred for about 2 hours at room temperature.
  • reaction product ((Z)-1 -pentol/butenylmethyl ether-product) was solved into 8 ml of 2-methyltetrahydrofuran (water-free).
  • step (b)) the (Z)-1 -pentol/butenylmethyl ether-product, was added dropwise to the Grignard solution.
  • the temperature of the reaction mixture was kept at a temperature of between 35 - 40 °C.
  • the reaction mixture was stirred at that temperature for about an hour.
  • the reaction mixture was stirred at a temperature of between 35 - 40 °C for about an hour, cooled to room temperature (20 - 25°C), and the reaction mixture was added to 67 g of a water/ice.
  • the mixture was stirred for about 2 hours at room temperature.

Landscapes

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

Abstract

La présente invention concerne un procédé amélioré de production de 3,7-diméthyl-9-(2,6,6-triméthyl-1-cyclohexèn-1-yl)-nona-2Z,7E-dien-4-yne-1,6-diol.
EP18743479.0A 2017-07-20 2018-07-19 Procédé de production de 3,7-diméthyl-9-(2,6,6-triméthyl-1-cyclohexèn-1-yl)-nona-2z,7e-dien-4-yne-1,6-diol Pending EP3655391A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17182234 2017-07-20
PCT/EP2018/069628 WO2019016315A1 (fr) 2017-07-20 2018-07-19 Procédé de production de 3,7-diméthyl-9-(2,6,6-triméthyl-1-cyclohexèn-1-yl)-nona-2z,7e-dien-4-yne-1,6-diol

Publications (1)

Publication Number Publication Date
EP3655391A1 true EP3655391A1 (fr) 2020-05-27

Family

ID=59383982

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18743479.0A Pending EP3655391A1 (fr) 2017-07-20 2018-07-19 Procédé de production de 3,7-diméthyl-9-(2,6,6-triméthyl-1-cyclohexèn-1-yl)-nona-2z,7e-dien-4-yne-1,6-diol

Country Status (3)

Country Link
EP (1) EP3655391A1 (fr)
CN (1) CN110914237A (fr)
WO (1) WO2019016315A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685338B (zh) * 2022-04-08 2023-09-12 上虞新和成生物化工有限公司 一种维生素a醋酸酯的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2451739A (en) 1945-10-18 1948-10-19 Hoffmann La Roche Process for the manufacture of pentaenes
US2920103A (en) * 1958-01-24 1960-01-05 Ortho Pharma Corp 11-monocis isomer of vitamin a
GB877556A (en) * 1958-04-23 1961-09-13 Pfizer & Co C Purification of a vitamin a intermediate
US3046310A (en) 1958-04-23 1962-07-24 Pfizer & Co C Oxenin intermediate and process for obtaining oxenin
CH481088A (de) * 1966-03-22 1969-11-15 Hoffmann La Roche Verfahren zur Herstellung eines isoprenoiden Alkohols
CN106588958B (zh) * 2015-10-14 2018-09-28 上虞新和成生物化工有限公司 一种连续制备炔醇双格氏试剂的生产系统及方法

Also Published As

Publication number Publication date
CN110914237A (zh) 2020-03-24
WO2019016315A1 (fr) 2019-01-24

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Owner name: DSM IP ASSETS B.V.