GB1578360A - Production of methyl varillyl ketone - Google Patents
Production of methyl varillyl ketone Download PDFInfo
- Publication number
- GB1578360A GB1578360A GB52296/77A GB5229677A GB1578360A GB 1578360 A GB1578360 A GB 1578360A GB 52296/77 A GB52296/77 A GB 52296/77A GB 5229677 A GB5229677 A GB 5229677A GB 1578360 A GB1578360 A GB 1578360A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- catalyst
- formula
- aqueous
- toluene
- 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.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/52—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition by dehydration and rearrangement involving two hydroxy groups in the same molecule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
(54) PRODUCTION OF METHYL VANILLYL KETONE
(71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State of New Jersey, United
States of America, of Rahway, New Jersey,
United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention provides a novel preparation of methyl vanillyl ketone from guaiacol.
Methyl vanillyl ketone has the formula:
It is an intermediate compound in the preparation of the hypertensive agent, L- a - methyl - 3,4 - dihydroxyphenylalanine.
The ketone (I) can be prepared from the substituted benzaldehyde, vanillin, or from a suitably substituted phenyl acetonitrile. These processes and/or the preparation of the hypertensile agent are disclosed in U.S. 3,344,023 and U.S. 3,366,679. Of the two known processes for preparing the ketone (I), the preferred process utilizes the vanillin starting material. Vanillin is expensive, and an alternative route to the ketone (I) using a less expensive readily available starting material has been sought.
The present process provides such a process, using guaicol, which has the formula:
as the starting material.
In accordance with the present invention, a compound having the formula:
is prepared by
(a) reacting a compound having the
formula:
with
in the presence of a Friedel Crafts catalyst to obtain
(b) reacting a compound III with a strong
base as herein defined in the substan
tial absence of oxygen, followed by
acidification, to obtain
(c) reducing compound IV with hydrogen
in the presence of a catalyst to obtain
and
(d) rearranging and dehydrating compound
V, e.g. by treatment with acid or base,
to obtain compound I.
Step (a) is a Friedel Crafts acylation.
While catalvsts such as SnCI, TiC14, ZnClp, FeCI or HF can be used, AlCI. is preferred.
The acvlation is most efficiently carried out when at least one mole of the catalyst (AICI) is provided for each of the reactants, II and (A). Reaction temperatures ranging from -10 C to 50"C can be used. The reaction is generally carried out in a solvent such as ethylene dichloride, nitrobenzene or carbon disulfide. The preparation of the bromo analogue of the formula III compound is described in the Journal of the American
Chemical Society 68, 1916 (1946).
In Step (b) the chloro compound III is converted to the corresponding hydoxy compound IV by treatment with an appropriate strong base, i.e. a base capable of effecting this conversion. The reaction is conveniently carried out in water as the reaction medium.
Any strong base, such as NaOH or KOH, may be used. The reaction temperature may
be varied from - 100C to 800C. A feature
of this reaction with base is that it be carried
out in the substantial absence of oxygen. If
oxygen is not substantially excluded, the yield
is reduced. After the reaction with base is
complete, the reaction mixture is cooled and
then is acidified with a strong acid, e.g.
H2SO4, HC1, H3PO4 etc. The product IV
may be isolated if desired. However, the
reaction mixture containing product IV can
conveniently be used directly in the next step
after simply adjusting the pH to the desired
level. The preparation of compound IV from
the corresponding a-acetoxy derivative is re
ported in the Journal of the American
chemical Society 61, 2204-2206 (1939).
Step (c) embodies catalytic reduction of
the IV compound. Any suitable reducing
system may be utilized. A preferred system
utilizes hydrogen and a heterogenous metal
containing catalyst such as Raney nickel, 60%
nickel on Kieselguhr, Pt/C or Pd/C. Raney
nickel is a preferred catalyst. The reduction
(or hydrogenation) is carried out on the
aqueous system containing the IV compound.
The pH of this aqueous system is adjusted
by addition of a suitable mineral acid to the
pH range proper for the particular catalyst
system used. In the case of the Raney nickel
catalyst, the reduction is best carried out in a non-basic medium with the system initially at about pH 4.5e Beginning at a much lower pH diminishes catalyst activity. Excessive byproduct formation occurs if the pH rises above about 7.5 during the hydrogenation. Reaction temperature may be varied in the range of 200C to 2000C with 700C to 900C being preferred. The hydrogen pressure may also be varied from atmospheric to 800 psig.
Step (d) involves a rearrangement of the
Formula V compound. The rearrangement is usually carried out in a liquid reaction medium in the presence of an acid or base. A preferred system involves adding an aqueous solution of Formula V to a two-phase mixture of aqueous acid and an immiscible solvent, such as benzene, CCl4, chlorobenzene or toluene, and removing H2O from rhe system by azeotropic distillation to maintain a constant volume. Under these conditions byproduct formation is minimized.
The product of the present process, namely the methyl vanillyl ketone of formula I, is used as an intermediate in the preparation of the antihypertensive agent a - methyl3,4 - dihydroxyphenyl alanine, which has the formula
The following example illustrates the process of the present invention. Temperatures are in C unless otherwise indicated.
EXAMPLE 1.
A. Preparation of a-Chloropropioguaiacone.
To an agitated slurry of 13.8 g anhvdrous aluminum chloride in 25 ml ethylenedichloride is added 6.7 g 2-chloropropionylchloride at ambient temperature. The mixture is stirred for an additional 15 minutes, then 6.0 g guaiacol is added dropwise under nitrogen with agitation at 15-200C.
The reaction mixture after aging at ambient temperature for 20 hours is quenched onto ice-water. The layers are separated and the aqueous phase is extracted with ethylene dichloride. The combined organic phase is washed with water, then the solvent is recovered in vacuo. The oily residue is recrystallized from a solvent mixture of 4 ml of ethylacetate and 20 ml cyclohexane. The crystalline a-chloropropioguaiacone m.p. 81 83 , is filtered and washed with a cold solvent mixture of 15% ethylacetate 85% cyclohexane, and dried in vacuo.
B. Preparation of a-Hydroxypropioguaiacone.
To a slurry of 11.61 g Ier-chloropropio- guaiacone in 110 ml of oxygen free water is added 100 ml 1.5 N sodium hydroxide in an inert atmosphere. The reaction mixture is stirred at 40-43 0C for four hours. After the solution has been coated to ambient temperature, the pH is adjusted to 4.2 by adding 30% sulfuric acid. The solution is decolorized by charcoal treatment and used directly in the next step.
If one desires, the pure a-hydroxypropioguaiacone can be crystallized by evaporation of part of the water, giving, after washing and drying, the known product, mp 1091100.
C. Preparation of 1 - (4 - Hydroxy - 3
Methoxyphenyl) - Propane - 1,2 diol.
An aqueous solution of a-hydroxypropio- guaiacone (from step B) is hydrogenated to 1 - (4 - hydroxy - 3 - methoxyphenyl)propane - 1,2 - diol at 800C and 90 p.s.i.
hydrogen over 1.Q1.2 g Raney nickel.
The mixture is cooled to room temperature after the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and the aqueous solution of diol is used directly in the next step.
D. Preparation of Methylvanillyl ketone
(MVK).
To a refluxing azeotropic mixture of 125 ml toluene and 100 ml 10% sulfuric acid is added an aqueous solution (~ 250 ml.) of 9.0 g 1 - (4 - hydroxy - 3 - methoxyphenyl)propane - 1,2 - diol (from step C) at such a rate that the volume of the aqueous phase remained constant during the addition, returning the toluene and separating the aqueous phase of the distillate by a Dean-Stark head.
The separation of the water is discontinued after - 250 ml is collected and the reaction mixture is refluxed for an additional hour.
After cooling the reaction mixture to room temperature the two phases are separated. The aqueous layer is extracted with toluene and the combined organic phase is washed with water and the toluene is removed in vacuo.
The concentrate is 86% pure methylvanillyl ketone by gc. assay and may be further purified by distillation, if desired.
WHAT WE CLAIM IS:
1. A process for preparing a compound having the formula
which comprises
(a) reacting a compound having the formula
with
in the presence of a Friedal Crafts catalyst to obtain
(b) reacting compound III with a strong
base as herein defined in the substantial
absence of oxygen, followed by acidifi
cation, to obtain
(c) reducing compound IV with hydrogen
in the presence of a catalyst to obtain
and (d) rearranging and dehydrating compound
V to obtain compound I.
2. A process as claimed in Claim 1, in which in step (a) the Friedel Crafts catalyst is step the Friedel A1Cls.
3. A process as claimed in Claim 1 or 2, in which in step (b) the strong base is NaOH or KOH.
4. A process as claimed in any preceding claim, in which in step (c) the catalyst is a heterogenous metal-containing catalyst.
5. A process as claimed in Claim 4, in which the reduction step (c) is carried out in an acidic aqueous system.
6. A process as claimed in Claim 5, in which the catalyst is Raney nickel and the pH of the aqueous system is not less than 4.5.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (16)
1. A process for preparing a compound having the formula
which comprises
(a) reacting a compound having the formula
with
in the presence of a Friedal Crafts catalyst to obtain
(b) reacting compound III with a strong
base as herein defined in the substantial
absence of oxygen, followed by acidifi
cation, to obtain
(c) reducing compound IV with hydrogen
in the presence of a catalyst to obtain
and (d) rearranging and dehydrating compound
V to obtain compound I.
2. A process as claimed in Claim 1, in which in step (a) the Friedel Crafts catalyst is step the Friedel A1Cls.
3. A process as claimed in Claim 1 or 2, in which in step (b) the strong base is NaOH or KOH.
4. A process as claimed in any preceding claim, in which in step (c) the catalyst is a heterogenous metal-containing catalyst.
5. A process as claimed in Claim 4, in which the reduction step (c) is carried out in an acidic aqueous system.
6. A process as claimed in Claim 5, in which the catalyst is Raney nickel and the pH of the aqueous system is not less than 4.5.
7. A process as claimed in any preceding
claim, in which in step (d) a strong mineral acid is used as catalytic agent.
8. A process as claimed in Claim 7, in which the acid is H2SO4.
9. A process as claimed in Claim 7 or 8, in which the compound V is added to the acid.
10. A process as claimed in Claim 1 sub stantiallv as hereinbefore described in the
Example.
11. A process comprising reacting a compound of Formula III in Claim 1 with a strong base in the substantial absence of oxygen to obtain a compound of Formula IV in Claim 1.
12. A process as claimed in Claim 11 carried out in an aqueous medium.
13. A process as claimed in Claim 11 or 12, in which the base is NaOH or KOH.
14. A process as claimed in Claim 11 substantially as hereinbefore described in the
Example.
15. A compound of Formula I in Claim 1, when prepared by a process as claimed in any one of Claims 1 to 10.
16. A compound of Formula IV in Claim 1, when prepared by a method as claimed in any one of Claims 11 to 14.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US75315176A | 1976-12-21 | 1976-12-21 | |
DE19782813330 DE2813330A1 (en) | 1976-12-21 | 1978-03-28 | METHOD OF MANUFACTURING A KETONE |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1578360A true GB1578360A (en) | 1980-11-05 |
Family
ID=25774159
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB52296/77A Expired GB1578360A (en) | 1976-12-21 | 1977-12-15 | Production of methyl varillyl ketone |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS5379834A (en) |
DE (1) | DE2813330A1 (en) |
GB (1) | GB1578360A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5810525A (en) * | 1981-06-15 | 1983-01-21 | Sagami Chem Res Center | Preparation of optical active 1-aromatic group-substituted-1-alkanones |
-
1977
- 1977-12-15 GB GB52296/77A patent/GB1578360A/en not_active Expired
- 1977-12-21 JP JP15302977A patent/JPS5379834A/en active Pending
-
1978
- 1978-03-28 DE DE19782813330 patent/DE2813330A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
DE2813330A1 (en) | 1979-10-11 |
JPS5379834A (en) | 1978-07-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4524217A (en) | Process for producing N-acyl-hydroxy aromatic amines | |
EP0022162B1 (en) | Process for producing disubstituted 4-hydroxycyclopentenones; monosubstituted cyclopentendiones and 4-hydroxycyclopentenones | |
US4139561A (en) | Novel substituted amino-aromatic acetylenes and their method of preparation | |
US4568763A (en) | Process for producing N-acyl-acyloxy aromatic amines | |
US5777172A (en) | Process for the preparation of benzophenthiones and benzophenones | |
US4560789A (en) | Process for producing 4-acetoxyacetanilide | |
Menegheli et al. | Carboxylation of arenes | |
US4203928A (en) | Process for the preparation of 2-nitrobenzaldehyde | |
EP0168908B1 (en) | Process for producing n-acyl-acyloxy aromatic amines | |
GB1578360A (en) | Production of methyl varillyl ketone | |
US4169858A (en) | Process for preparing a ketone | |
JPS6365057B2 (en) | ||
JPH08500360A (en) | Method for producing phenyl terephthalic acid | |
EP0436800B1 (en) | Process for producing isocyanate compound | |
EP0194849B1 (en) | Improved process for producing n-acyl-acyloxy aromatic amines | |
US4697024A (en) | Medroxalol intermediates | |
US5072037A (en) | Process for the preparation of 2-(4-chlorophenyl)-3-methylbutyric acid | |
EP0203557B1 (en) | Process for the preparation of (6-methoxy-2-naphthyl)-(1-bromoethyl)-ketone and its derivatives | |
JP2738093B2 (en) | Method for producing tertiary butylbenzaldehyde isomer mixture | |
EP1554266B1 (en) | Process for preparing 2,5-disubstituted 3-alkylthiophenes | |
JP3535637B2 (en) | Method for producing cis-3,3,5-trimethylcyclohexanol | |
US4436939A (en) | Process for producing 1-(p-prenylphenyl)ethanol | |
JP3177420B2 (en) | Method for producing 4-methoxy-2,2 ', 6'-trimethyldiphenylamine | |
EP0331422A2 (en) | Method of preparing 2-acylresorcinols | |
JPH0273033A (en) | Production of 4, 4-dimethyl-1-(p-chlorophenyl) pentane-3-one |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |