CN113061086B - Preparation method of long-chain aliphatic dicarboxylic acid mono-tert-butyl ester - Google Patents
Preparation method of long-chain aliphatic dicarboxylic acid mono-tert-butyl ester Download PDFInfo
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- CN113061086B CN113061086B CN202010001797.2A CN202010001797A CN113061086B CN 113061086 B CN113061086 B CN 113061086B CN 202010001797 A CN202010001797 A CN 202010001797A CN 113061086 B CN113061086 B CN 113061086B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention provides the method for obtaining the long-chain aliphatic dicarboxylic acid mono-tert-butyl ester by mono-hydrolysis of the long-chain aliphatic dicarboxylic acid di-tert-butyl ester by controlling the reaction conditions of mono-hydrolysis, which has the advantages of low raw material cost, higher yield and simple post-treatment method, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of long-chain aliphatic dicarboxylic acid mono-tert-butyl ester.
Background
Glucagon-like peptide-1 (GLP-1) agonists as novel hypoglycemic agents are effective in controlling blood glucose while significantly reducing the incidence of hypoglycemic events and also have the benefit of significantly reducing body weight, reducing the risk of cardiovascular events. However, natural GLP-1 is susceptible to degradation in vivo, resulting in a short half-life, and thus chemical modification of GLP-1 to obtain long-acting GLP-1 agonists has been a problem that industry has been struggling to solve.
International patent publication WO2006097537A2 discloses a class of chemically modified GLP-1 analogs with a longer half-life that employ a partial acylation at the lysine residue at position 26, containing a long chain acidic group at the terminus, for example:wherein I is 12, 13, 14, 15, 16, 17, 18, 19 or 20, which long chain acidic group can be prepared from the corresponding long chain aliphatic dicarboxylic acid mono-tert-butyl ester intermediate.
The existing synthesis of long-chain aliphatic dicarboxylic acid mono-tert-butyl ester usually uses the corresponding long-chain aliphatic dicarboxylic acid for mono-esterification, but the yield is only 20-40% (WO 2005082404A, WO2004035624A, CN 105001140B) due to the overlong carbon chain and lack of selectivity of mono-esterification, and the yield is only on the gram scale, so that the requirement of industrial production can not be met.
Disclosure of Invention
In order to solve the problem of low yield of long-chain aliphatic monocarboxylic acid mono-tert-butyl ester prepared in the prior art, the invention provides a method for obtaining long-chain aliphatic dicarboxylic acid mono-tert-butyl ester (a compound of formula (I)) through mono-hydrolysis of long-chain aliphatic dicarboxylic acid di-tert-butyl ester, which comprises the following steps:
which is composed of a compound of the formula (II)
Is prepared by single hydrolysis under the condition of alkaline reagent, wherein n is an integer within 8-18.
In some embodiments, n is an even number within 8-18.
In other embodiments, n is 16 or 18.
In other embodiments, the alkaline agent is barium hydroxide or a hydrate thereof, preferably barium hydroxide octahydrate; the molar ratio of alkaline reagent to compound of formula (II) is 1-3:1, preferably 2:1.
In other embodiments, the reaction solvent is methanol or a mixed solvent of methanol and t-butanol.
In other embodiments, the reaction solvent is a mixed solvent of methanol and t-butanol, the volume ratio of t-butanol to methanol being 1 to 1.2:1.
In other embodiments, the reaction temperature is 25 to 50 ℃, preferably 28 to 30 ℃.
When n is even, the aforementioned compound of formula (II) can be prepared by the following steps:
esterifying the compound of the formula (III) under the condition of trifluoroacetic anhydride and tertiary butanol to obtain the compound of the formula (IV),
the compound of the formula (IV) is subjected to coupling reaction under the conditions of nickel chloride hexahydrate, 2':6', 2' -terpyridine and zinc powder to prepare the compound of the formula (II),
alternatively, the aforementioned compound of formula (II) may also be prepared by the steps of:
the compound of the formula (III) is subjected to coupling reaction under the conditions of nickel chloride hexahydrate, 2':6', 2' -terpyridine and zinc powder to prepare the compound of the formula (V),
esterifying the compound of the formula (V) under the condition of trifluoroacetic anhydride and tertiary butanol to obtain a compound of the formula (II),
when n is an odd number, the compound of formula (II) can be obtained by esterifying the corresponding diacid under the conditions of trifluoroacetic anhydride and tertiary butanol.
The invention provides a novel method for synthesizing long-chain aliphatic dicarboxylic acid mono-tert-butyl ester by controlling the reaction conditions of single hydrolysis, so that the conversion rate of the target product of single hydrolysis can reach more than 80%, the single-step reaction yield is more than 70%, the product purity can reach more than 99%, the product purity is amplified to the kilogram scale, the raw material cost is low, the post-treatment method is simple, the operation such as column chromatography is not needed, and the method is suitable for industrial production.
Detailed Description
EXAMPLE 1 preparation of mono-tert-butyl eicosadioate
Step one: preparation of tert-butyl 10-bromodecanoate
10-bromodecanoic acid (5.7 kg,1.0 eq.) and DCM (22.8L, 4V) were added to the reaction vessel; trifluoroacetic anhydride (10.7 kg,2.2 eq.) was added dropwise at 0deg.C and stirred for 0.5h; t-BuOH (5.89 kg,3.5 eq.) was added at 0-10℃and stirring was continued for 2h. Quenched with water, left to stand for separation, the organic phase was washed with water (4 V.times.5) and concentrated to give 6.914kg of a dark brown liquid with a purity of 98.9% and a yield of 98%.
Step two: preparation of di-tert-butyl eicosadioate
Tert-butyl 10-bromodecanoate (6.79 kg,1.0 eq.) zinc powder (1.52 kg,1.05 eq.) and DMF (26L) were added to the reaction kettle under nitrogen; adding NiCl 2 .6H 2 O (105.1 g,0.02 eq.) and 2,2':6', 2' -terpyridine (103.1 g,0.02 eq.) are stirred at 35-45℃for 10h. Dripping 1.8M HCl (20L) at 25-30deg.C, and stirring for 2-4h; filtering, washing with water (0.5V) and drying to obtain 9.95kg of off-white solid with purity of 94.9% and yield of 99%.
Step three: preparation of mono-tert-butyl eicosadioate
Ba (OH) 2 .8H 2 O (3.1 kg,1.8 eq.), di-tert-butyl eicosanate (2.5 kg,1.0 eq.) tert-butanol (45L) and methanol (37.5L) were added to the reactor and stirred for 30h at 28-30 ℃. Centrifugal filtration, adding filter cake and toluene (20V) into a reactor, stirring for 2h, adding 1M HCl (10V) and water (10V), separating liquid, concentrating the organic phase into yellow solid, washing with methanol (20L), filtering and drying to obtain 1698g white solid, purity 99.1% and yield 77.5%.
EXAMPLE 2 preparation of mono-tert-butyl octadecanedioate
Step one: preparation of octadecanedioic acid
9-Broononic acid (1.29 kg,5.44mol,1.0 eq.) zinc powder (730 g,2.05 eq.) and DMF (26L) were added to the reaction vessel under nitrogen; adding NiCl 2 .6H 2 O (65 g,0.05 eq.) and 2,2':6', 2' -terpyridine (63.4 g,0.05 eq.) were stirred at 35-45℃for 8h. Dripping 1.8M HCl (20L) at 25-30 ℃ and stirring for 2-4h; filtering, washing with water (0.5V) and drying to obtain 1.7kg white solid with purity of 95.4% and yield of 99%.
Step two: preparation of Di-tert-butyl octadecanedioate
Octadecanedioic acid (1.69 kg,1.0 eq.) and THF (9 l,5.3 v) were added to the reaction vessel; trifluoroacetic anhydride (3.39 kg,3.0 eq.) was added dropwise at 0℃and stirred for 1h, and t-BuOH (1.91 kg,4.8 eq.) was added dropwise at 0-10 ℃. Stirring at 25-28deg.C for 5 hr. NaHCO 3 (2.7 kg,6.0 eq.) and water (20 l,12 v); dripping NaHCO3 water solution into a reaction kettle, and stirring for 1h at 15-20 ℃; the mixture was filtered and dried to obtain 2.13kg of pale yellow solid, and the yield was 92.9%. Step three: preparation of mono-tert-butyl octadecanedioate
Ba (OH) 2 .8H 2 O (2.95 kg,1.7 eq.), di-tert-butyl octadecanedioate (2.34 kg,1.0 eq.) tert-butanol (25L) and methanol (25L) were added to the reaction vessel and stirred at 28-30℃for 20h. Centrifugal filtration, adding filter cake and toluene (20V) into a reactor, stirring for 2h, adding 1M HCl (10V) and water (10V), separating liquid, concentrating the organic phase into yellow solid, washing with methanol (20L), filtering and drying to obtain 1448g white solid with purity of 99.5% and yield of 71.0%.
EXAMPLE 3 Single hydrolysis condition screening experiment
The screening results of the single hydrolysis reaction conditions are shown in Table 1 with reference to the method of step three of example 1.
TABLE 1
Claims (3)
1. A process for the preparation of a compound of formula (I):
which is composed of a compound of the formula (II)
Is prepared by single hydrolysis under the condition of alkaline reagent, wherein n is 16 or 18;
the alkaline reagent is barium hydroxide octahydrate, and the molar ratio of the alkaline reagent to the compound of the formula (II) is 1-3:1;
the reaction solvent is a mixed solvent of methanol and tertiary butanol, and the volume ratio of the tertiary butanol to the methanol is 1-1.2:1;
the reaction temperature is 28-30 ℃.
2. The method of manufacturing according to claim 1, further comprising the steps of:
esterifying the compound of the formula (III) under the condition of trifluoroacetic anhydride and tertiary butanol to obtain the compound of the formula (IV),
the compound of the formula (IV) is subjected to coupling reaction under the conditions of nickel chloride hexahydrate, 2':6', 2' -terpyridine and zinc powder to prepare the compound of the formula (II),
3. the method of manufacturing according to claim 1, further comprising the steps of:
the compound of the formula (III) is subjected to coupling reaction under the conditions of nickel chloride hexahydrate, 2':6', 2' -terpyridine and zinc powder to prepare the compound of the formula (V),
esterifying the compound of the formula (V) under the condition of trifluoroacetic anhydride and tertiary butanol to obtain a compound of the formula (II),
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466679A (en) * | 2006-03-30 | 2009-06-24 | 田边三菱制药株式会社 | A process for preparing tetrahydroquinoline derivatives |
| CN109776323A (en) * | 2019-01-28 | 2019-05-21 | 富乐马鸿凯（大连）医药有限公司 | A kind of method that efficient selective prepares the fat diacid list tert-butyl ester |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466679A (en) * | 2006-03-30 | 2009-06-24 | 田边三菱制药株式会社 | A process for preparing tetrahydroquinoline derivatives |
| CN109776323A (en) * | 2019-01-28 | 2019-05-21 | 富乐马鸿凯（大连）医药有限公司 | A kind of method that efficient selective prepares the fat diacid list tert-butyl ester |
Non-Patent Citations (1)
| Title |
|---|
| Hei Man Cheng 等.En Route to a Molecular Sheaf: Active Metal Template Synthesis of a [3]Rotaxane with Two Axles Threaded through One Ring.《Journal of the American Chemical Society》.2011,第133卷附加信息第S9页第2段. * |
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