A process for the preparation of alcohol compounds
The described process efficiently converts aldehydes to alcohol compounds using aliphatic ether solvents and reduced catalysts, addressing inefficiencies in existing methods by achieving high yield, purity, and solvent recovery, thus being industrially viable.
Patent Information
- Application Number
- PCT/IB2025/057964
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-08-05
- Filing Date
- 2025-08-05
- Publication Date
- 2026-02-12
AI Technical Summary
Existing processes for preparing 4-hydroxy substituted alcohol compounds, such as vanillyl alcohol, are inefficient, uneconomical, and produce impurities like 3,4-dihydroxybenzaldehyde, with low solvent recovery and high catalyst usage, making them unsuitable for industrial applications.
A process involving the reduction of aldehydes like 4-hydroxy-3-methoxybenzaldehyde to alcohol compounds using a lower amount of catalyst and aliphatic ether solvents, avoiding the formation of impurities and enabling high solvent recovery.
The process achieves high yield and purity of alcohol compounds with minimal impurities, efficient solvent recovery, and cost-effectiveness, making it suitable for industrial use.
Smart Images
Figure IB2025057964_12022026_PF_FP_ABST
Abstract
Description
[0001] TITLE: A PROCESS FOR THE PREPARATION OF ALCOHOL COMPOUNDS
[0002] Field of the invention
[0003] The present invention relates to a process for preparation of alcohols from aldehydes and ketones. The present invention particularly relates to a process of preparation of 4-(hydroxymethyl)-2 -methoxy phenol having high purity and high yield.
[0004] Background of the invention:
[0005] 4-Hydroxy substituted alcohol compounds are used as intermediate compounds that are used as an intermediate compound in various industrial applications in pharmaceutical as well as agrochemical industry. Compounds such as substituted 4-hydroxybenzyl alcohols are also used as flavor and fragrance agents as an additive in various products.
[0006] One of these compounds, 4-hydroxy-3 -methoxybenzyl alcohol (Vanillyl alcohol) is of great commercial interest which is manufacture and used across various industries in diverse applications. It is a member of guaiacols and a member of benzyl alcohols. It is used as flavoring agent in pharmaceutical products and has also applications in preparing renewable epoxy thermosets. It can be used in the food industry as a natural preservative, It is also used as one of the key intermediate compound for preparing agrochemically active ingredients such as Mandipropamid. Vanillyl alcohol is derived from vanillin by reducing the vanillin using various reducing conditions at industrial scale.
[0007] US2414120 discloses process for conversion of vanillin to its vanillyl alcohol which comprises reacting vanillin in presence of catalytic silver in aqueous alkaline solution, such as sodium hydroxide solution.
[0008] US 10246544 describes the process of preparing vanillyl alcohol from vanillin in ethanol solvent using sodium borohydride as a solution in aqueous sodium hydroxide. The reaction is carried out at lower temperature. In alcoholic solvent, such as methanol or ethanol, NaBFU decomposes over time to give the respective borates. Therefore, the method requires almost 1.5 to 2.0 equivalents of sodium borohydride with respect to vanillin, thus making the process uneconomical.
[0009] Bull. Chem. Soc. Jpn., 78, 307- -315 (2005) discloses preparation of alcohols using NaBFU in THF-water solvent system. The method involves reducing aldehydes, ketones at room temperature. Since the solvents are miscible, recovery and re-use of solvents are not efficient hence not industrially viable. Further, the catalyst used, such as NaBFU decomposes in presence of water to form sodium hydroxide and hydrogen while carrying out the reaction. The sodium hydroxide thus formed can convert alkoxy group of the aldehyde substrates, such as vanillin, 4- Methoxybenzaldehyde, 3 -Methoxybenzaldehyde and the like to the corresponding hydroxy compound as an impurity.
[0010] Therefore, there is a need for a process for preparing alcohol compounds which can overcome the drawbacks of prior art process.
[0011] The inventors of the present invention have developed a process in which alcohol compounds have been prepared from aldehydes such as 4-Hydroxy-3- methoxybenzaldehyde (vanillin) using lower amount of catalyst and industrially suitable solvent system, thereby making the process clean, efficient and industrially viable.
[0012] Object of the invention
[0013] It is an object of the present invention to provide a process for the preparation of an alcohol compounds of Formula (I) from the corresponding aldehydes and ketones.
[0014] Formula (I) Another object of the present invention is to provide a process for the preparation of alcohol compounds of formula (I) with significant recovery of solvent.
[0015] Another object of the present invention is to provide alcohol compounds substantially free from impurities.
[0016] Yet another object of the present invention to provide an efficient and industrially viable process for the preparation of alcohol compounds.
[0017] Summary of invention:
[0018] An aspect of the present invention is to provide a process for preparation of an alcohol compound of Formula (I),
[0019] Formula (I) wherein R may be selected from hydrogen or Cl to C8 substituted or unsubstituted alkyl group, the process comprising: reducing compound of Formula (II) to compound of Formula (I) in an aliphatic ether solvent,
[0020] Form ula (II) wherein R has same meaning as above.
[0021] Another aspect of the present invention is to provide the process for preparation of alcohol compound of Formula (I),
[0022] Formula (I) wherein R may be selected from hydrogen or Cl to C8 substituted or un- substituted alkyl group, the process comprising: reducing compound of Formula (II) into compound of Formula (I) using a reducing agent in an aliphatic ether solvent,
[0023] Form ula (II) wherein R has same meaning as above, and wherein the process provides at least 80 % of solvent recovery.
[0024] Another aspect of the present invention is to provide alcohol compound of Formula (I), which is substantially free of impurities, wherein the impurities comprise of 3,4- Dihydroxybenzaldehyde of Formula (III) or its related compounds.
[0025] Formula (III)
[0026] Detailed Description of the invention:
[0027] In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as commonly understood by the person of ordinary skill in the art to which this invention pertains.
[0028] As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
[0029] As used in this specification, the term “substantially free of impurities” refers to alcohol compound of Formula (I) containing less than or equal to 1 % of unreacted synthetic intermediates, reagents, solvents, organic and / or inorganic products of side reactions, organic and / or inorganic salts and / or other undesired materials.
[0030] As used in this specification the term “non-aqueous solvent system” refers to the solvent system, wherein water is not added and the moisture content of the solvent system is less than 2 %, preferably less than 1 %.
[0031] As used herein, “compound of Formula (I), substantially free of impurities” refers to the said compound having less than 1 % of impurities, wherein the impurities comprise of 3,4-Dihydroxybenzaldehyde of Formula (III) or its related compounds.
[0032] Formula (III)
[0033] The invention is now described in detailed with respect to the preferred, however non-limiting embodiments. It has now been surprisingly found that when aldehyde compounds such as compound of Formula (II) are converted to alcohol compound such as compounds of Formula (I), using aliphatic ether solvent, in a non-aqueous solvent system, the product obtained is free of unwanted byproducts and impurities which may be formed while following known methods, especially in presence of water as a cosolvent. The process of the present invention also provides advantages in terms of solvent recovery which can be reused and recycled for the next batch, reducing the cost of the process.
[0034] Accordingly, in an embodiment, the present invention provides a process for preparation of alcohol compound of Formula (I),
[0035] Formula (I) wherein R may be selected from hydrogen or Cl to C8 substituted or unsubstituted alkyl group, the process comprising: reducing compound of Formula (II) to compound of Formula (I) in an aliphatic ether solvent,
[0036] Form ula (II) wherein R has same meaning as above.
[0037] In an embodiment, the compound of Formula (II) is selected from the carbonyl compounds comprising 4-hydoxy-3-methoxybenzaldehyde, 4-hydoxy-3- ethoxybenzaldehyde, 4-hydoxy-3-propoxybenzaldehyde; preferably 4-hydoxy-3- methoxybenzaldehyde is used.
[0038] In another embodiment, aliphatic ether solvent is selected from methyl tertiary butyl ether, ethyl -tert-butyl ether, dimethyl ether, ethyl methyl ether, diethyl ether, glycol ether such as diethylene glycol dibutyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, the dimethyl and diethyl ethers of ethylene glycol and diethylene glycol, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, di-n-propyl ether, dipropyleneglycol methyl ether, Ethylene glycol monopropyl ether; cyclic ethers such as tetrahydrofuran, 2-Methyl-tetrahydrofuran; the preferred ether solvent is methyl tertiary butyl ether.
[0039] In an embodiment, preparation of alcohol compound of Formula (I) is carried out in a non-aqueous solvent system, comprising aliphatic ether solvent.
[0040] In an embodiment, preparation of alcohol compound of Formula (I) is carried out in a non-aqueous solvent system, comprising aliphatic ether solvent, avoiding the formation of impurities, such as 3,4-Dihydroxybenzaldehyde of Formula (III) or its related compounds.
[0041] Formula (III)
[0042] In an embodiment, the reduction of Formula (II) to compound of Formula (I) is carried out in presence of suitable reducing agent which is selected from group comprising aluminum hydrides, borohydrides or borane complexes.
[0043] In an embodiment the reduction of compound of Formula (II) to compound of Formula (I) is carried out in presence of suitable reducing agent which may be selected from aluminum hydrides such as lithium aluminium hydride, diisobutylaluminium hydride; borohydrides such as sodium borohydride, lithium borohydride, potassium borohydride, sodium cyanoborohydride; metal hydrides such as sodium hydride, zirconocene chloride hydride; boranes, such as borane ammonia complex, borane trimethylamine complex; preferably sodium borohydride is used.
[0044] In accordance with the above embodiment, the reducing agent used is 0.1 to 2.0 equivalent with respect to compound of Formula (II), preferably the reducing agent used is 0.1 to 1.0 equivalent.
[0045] In an embodiment, the reducing agent is added to the reaction mass in a lot wise manner.
[0046] In an embodiment, the reducing agent is added to the reaction mass in one lot.
[0047] In another embodiment, the reaction is carried out at a temperature range of about 20°C to about 50°C, preferably from about 25°C to about 40°C.
[0048] In another embodiment, the present invention provides a process for preparation of 4-(hydroxymethyl)-2-methoxy phenol of Formula (la),
[0049] Formula (la) the process comprising: reducing 4-hydroxy-3 -methoxy benzaldehyde of Formula (Ila) to 4- (hydroxymethyl)-2-methoxy phenol of Formula (la) using sodium borohydride in methyl tertiary butyl ether solvent.
[0050]
[0051] In another embodiment, the present invention provides the process for preparation of alcohol compound of Formula (I),
[0052] Formula (I) wherein R may be selected from hydrogen or Cl to C8 substituted or un- substituted alkyl group, the process comprising: reducing compound of Formula (II) into compound of Formula (I) using a reducing agent in an aliphatic ether solvent,
[0053] Formula (II) wherein R has same meaning as above, and wherein the process provides at least 80 % of solvent recovery of aliphatic ether solvent
[0054] The compound of Formula (I) is prepared according to the process described hereinabove wherein the process involves recovering the aliphatic ether solvent used during the reaction. In accordance with above embodiment, at least 85 % aliphatic ether solvent is recovered.
[0055] In accordance with above embodiment, at least 90 % aliphatic ether solvent is recovered.
[0056] In an embodiment, aliphatic ether solvent may be recovered by using methods such as distillation and fractionation.
[0057] In another embodiment, the present invention provides a compound of Formula (I) which is substantially free of impurities, wherein the impurities comprise of 3,4- Dihydroxybenzaldehyde of Formula (III) or its related compounds.
[0058] Formula (III)
[0059] In another embodiment, the present invention provides a compound of Formula (I) comprising less than 1 % of 3,4-Dihydroxybenzaldehyde of Formula (III) or its related compounds.
[0060] In another embodiment, the present invention provides a compound of Formula (I) comprising less than 0.5 % of 3,4-Dihydroxybenzaldehyde of Formula (III) or its related compounds.
[0061] Analytical methods:
[0062] Samples were analyzed on high performance liquid chromatograph (HPLC) with UV detector using SB- C8 (250 x 4.6 mm, 5 micron). Examples:
[0063] The embodiments of the present invention are illustrated by below given examples. However, the scope of the present invention is not to be construed to be limited by the examples.
[0064] Example 1: Preparation of 4-(hydroxymethyl)-2-methoxy phenol:
[0065] Methyl tertiary butyl ether (743 ml) was charged in the reactor, followed by charging 4-hydroxy-3 -methoxy benzaldehyde (150 g; 0.986 moles) at 25°C to 30°C. The reaction mass was heated to 35°C to 40°C. Sodium borohydride (22.37 g; 0.591 moles) was added in lot wise manner over a period of 2 hours. The reaction mass was stirred at 30°C to 35°C for 2 hours. The reaction mass was cooled to 5°C to 10°C with gradual addition of water (450 ml) in reaction mass over a period of 2 to 3 hours. 30% cone. HC1 (55 ml) was added to this diluted reaction mass to adjust the pH to 6-6.5. The solids thus obtained were filtered and washed with water and Methyl tertiary butyl ether (200 ml). Wet cake obtained was dried at 55°C to 60°C under vacuum to get 4-(hydroxymethyl)-2-methoxy phenol (137 g; yield 90%). Formation of an impurity, 3,4-Dihydroxybenzaldehyde of Formula (III) was not detected. Methyl tertiary butyl ether from the filtrate was subjected to layer separation and was recovered 840 ml) by distillation. Recovered MTBE solvent - 89 %.
[0066] Example 2: Preparation of 4-(hydroxymethyl)-2-methoxy phenol using aqueous solvent system (THE- water solvent system- comparative example):
[0067] Tetrahydrofuran(THF) (112 ml) was charged in the reactor. 4-hydroxy-3 -methoxy benzaldehyde (25 g; 0.16 moles) at 25°C to 30°C was charged, followed by charging water (3 ml). Sodium borohydride (4 g; 0.6 moles) was added in lot wise manner over a period of 1 hour. The reaction mass was stirred at 25°C to 30°C for 2 hours. Water (27 ml) was added to the reaction mass, followed by addition of 15 % HC1 (20 g) to adjust the pH to 6-6.5. The reaction mass was heated to 40-45°C and THF and water were distilled out under vacuum. Concentrated mass which was obtained was diluted with water (25 ml) and cooled to 10°C to 15°C. The solids thus obtained were filtered and washed with cold water. Wet cake obtained was dried at 45°C to 50°C to give 4-(hydroxymethyl)-2-methoxy phenol (20.7 g; yield 82%). 3,4-Dihydroxybenzaldehyde of Formula (III)- 0.989 % (A / A). The distilled aqueous THF was further subjected to dehydration by fractional distillation; THF recovered was 77 ml (68 % solvent recovery).
[0068] Example 3: Preparation of 4-(hydroxymethyl)-2-methoxy phenol using aqueous solvent system (Me-THF-water solvent system- comparative example):
[0069] 2-Methyl-Tetrahydrofuran(2-Me-THF) (117 ml) was charged in the reactor. 4- hydroxy-3 -methoxy benzaldehyde (25 g; 0.16 moles) at 25°C to 30°C was charged, followed by charging water (3 ml). Sodium borohydride (4 g; 0.6 moles) was added in lot wise manner over a period of 1 hour. The reaction mass was stirred at 25°C to 30°C for 2 hours . Water (27 ml) was added to the reaction mass. 15 % HC1 (20 g) was added to reaction mass to adjust the pH to 6-6.5. The reaction mass was heated to 40-45°C and 2-Me-THF and water was distilled out under vacuum. Concentrated mass which was obtained after completion of reaction was diluted with water (25 ml) and cooled to 10°C to 15°C. The solids thus obtained were filtered and washed with cold water. Wet cake obtained was dried at 45°C to 50°C to give to give 4- (hydroxymethyl)-2-methoxy phenol (17.22 g; yield 68 %). 3,4-
[0070] Dihydroxybenzaldehyde of Formula (III)- 0.77 % (A / A). The distilled aqueous 2- Me-THF was further subjected to dehydration by fractional distillation; 2-Me-THF recovered was 86 ml (74 % solvent recovery).
[0071] Above performed experiments are summarized in below table:
[0072] From the above table it is evident that the process of the present invention as exemplified in example 1 provides the compound of formula (I) with better yield as compared to example 2 and 3. Additionally example 2 and 3 also suffer from low solvent recovery as compared to example 1 of present invention.
[0073] Advantages of the present invention:
[0074] The preparation method alcohol compound of present invention simple to operate. • The process provides end product devoid of any impurities.
[0075] • The solvent recovery is high which helps in recycling the solvent, making the process cost effective.
[0076] • The yield of the product is high, making the process industrially suitable.
[0077] • The process uses less amount of reducing agent for the preparation of alcohol compound from the corresponding aldehyde.
Claims
CLAIMS:
1. A process for preparation of an alcohol compound of Formula (I),Formula (I) wherein R may be selected from hydrogen or Cl to C8 substituted or unsubstituted alkyl group, the process comprising: reducing compound of Formula (II) to compound of Formula (I) in an aliphatic ether solvent,Form ula (II) wherein R has same meaning as above.
2. The process as claimed in claim 1, where the reaction is carried out in a non-aqueous solvent system, comprising aliphatic ether solvent.
3. The process, as claimed in claim 1, wherein the aliphatic ether solvent is selected from methyl tertiary butyl ether, ethyl -tert-butyl ether, dimethyl ether, ethyl methyl ether, diethyl ether, glycol ether such as diethylene glycol dibutyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, the dimethyl and diethyl ethers of ethylene glycol and diethylene glycol, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, di-n-propyl ether, dipropyleneglycol methyl ether, Ethyleneglycol monopropyl ether; cyclic ethers such as tetrahydrofuran, 2-Methyl- tetrahydrofuran.
4. The process, as claimed in claim 1, wherein the reducing agent is selected from the group comprising of aluminum hydrides, borohydrides or borane complexes.
5. The process, as claimed in claim 1, wherein the reaction is carried out at a temperature range of from about 20°C to about 50°C.
6. A process for preparation of 4-(hydroxymethyl)-2-methoxy phenol, the process comprising: reducing 4-hydroxy-3 -methoxy benzaldehyde to 4-(hydroxymethyl)-2- methoxy phenol using sodium borohydride in methyl tertiary butyl ether solvent.
7. A process for preparation of an alcohol compound of Formula (I),Formula (I) wherein R may be selected from hydrogen or Cl to C8 substituted or unsubstituted alkyl group, the process comprising: reducing compound of Formula (II) to compound of Formula (I) in an aliphatic ether solvent, and wherein said process provides at least 80 % of solvent recovery.
8. The process as claimed in claim 7, wherein said recovery of aliphatic ether solvent is done by method such as distillation or fractionation.
9. A compound of Formula (I) comprising less than 0.5 % of 3,4- Dihydroxybenzaldehyde of Formula (III) or its related compounds.Formula (III)