阅读说明：本技术 一种生物素中间体的合成方法 (Synthesis method of biotin intermediate ) 是由 张兴贤 张洪波 刘洪涛 于 2019-08-05 设计创作，主要内容包括：本发明属于药物化学合成领域,具体公开了一种生物素中间体5-((3aS,6aR)-1,3-二苄基-4-羟基-2-氧代己基-1H-呋喃并[3,4-d]咪唑-4-基)-5-烯酸的合成方法,包括：先以(3aS,6aR)-1,3-二苄基四氢-1H-噻吩并[3,4-d]咪唑-2,4-二酮为起始原料,与特定Normant’s试剂XMg(CH<Sub>2</Sub>)<Sub>5</Sub>OMgCl进行格氏加成反应,再在氮氧化物和氧化剂的作用下进行绿色催化氧化制得。本发明方法的反应条件温和、操作简便、收率高、化学选择性好、生产成本低,制得的生物素中间体经过一步反应脱去双苄基即可制得生物素,大大简化了生物素的生产流程。(The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly discloses a biotin intermediate 5- ((3aS, 6aR) -1, 3-dibenzyl-4-hydroxy-2-oxohexyl-1H-furo [3,4-d ]]A method for synthesizing imidazol-4-yl) -5-enoic acid comprising: firstly, (3aS,6aR) -1, 3-dibenzyl tetrahydro-1H-thieno [3,4-d]Imidazole-2, 4-diones as starting material, with specific Normant's reagent XMg (CH) 2 ) 5 And carrying out Grignard addition reaction on the OMgCl, and carrying out green catalytic oxidation under the action of a nitrogen oxide and an oxidant. The method has the advantages of mild reaction conditions, simple and convenient operation, high yield, good chemical selectivity and low production cost, and the prepared biotin intermediate can be used for removing the dibenzyl group through one-step reaction to prepare the biotin, thereby greatly simplifying the production process of the biotin.)

1. A method for synthesizing a biotin intermediate, comprising: performing Grignard addition reaction on a compound shown in a formula (I) and a Norman's reagent, and performing catalytic oxidation on the obtained compound shown in a formula (II) under the action of nitric oxide and an oxidant to obtain a biotin intermediate shown in a formula (III), wherein the specific reaction formula is as follows:

The Normant's reagent is XMg (CH)₂)₅OMgCl, wherein X is halogen Cl, Br or I.

2. The method of synthesizing a biotin intermediate as claimed in claim 1, wherein the Normant's reagent is ClMg (CH)₂)₅OMgCl。

3. The method for synthesizing the biotin intermediate as claimed in claim 1, wherein the molar ratio of the compound represented by the formula (I) to the Normant's reagent is 1: 1.2 to 3.0.

4. The method for synthesizing a biotin intermediate as claimed in claim 1, wherein said nitroxide compound is any one or more of 2,2,6, 6-tetramethylpiperidine nitroxide, 2-oxo-2-azaadamantane and azabicyclo [ 3.3.1N-oxyl ] nonylmethoxy nitroxide.

5. The method for synthesizing biotin intermediate according to claim 1, wherein the oxidizing agent is NaClO or NaClO₂、Ca(ClO)₂、Ca(ClO₂)₂And NaBrO.

6. The method for synthesizing the biotin intermediate as claimed in claim 1, wherein the molar ratio of the compound represented by the formula (I), the nitroxide compound and the oxidant is 1: 0.01-0.15: 1 to 5.

7. The method for synthesizing the biotin intermediate as claimed in any one of claims 1 to 6, which comprises the following steps:

(1) Dissolving a compound shown as a formula (I) in an organic solvent A, dropwise adding a Normant's reagent at-10-70 ℃ for reacting for 5-15 h, and carrying out post-treatment to obtain a compound shown as a formula (II);

(2) Dissolving the compound shown in the formula (II) obtained in the step (1), an oxynitride and an oxidant in an organic solvent B, reacting for 4-10 h at 10-60 ℃, and performing post-treatment to obtain the biotin intermediate shown in the formula (III).

8. the method for synthesizing biotin intermediate according to claim 7, wherein the organic solvent A is toluene, diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran.

9. the method for synthesizing the biotin intermediate according to claim 7, wherein the organic solvent B is dichloromethane, chloroform, toluene, acetonitrile or tetrahydrofuran.

Technical Field

The invention belongs to the field of chemical synthesis of medicines, and particularly relates to a synthesis method of a biotin intermediate 5- ((3aS, 6aR) -1, 3-dibenzyl-4-hydroxy-2-oxohexyl-1H-furo [3,4-d ] imidazole-4-yl) -5-olefine acid.

Background

Biotin, also known as vitamin H, is a water-soluble vitamin that is found primarily in the animal's viscera, milk, egg yolk and yeast. Biotin plays an important role in metabolism of living organisms as a coenzyme for various carboxylases in living organisms. If the body is deficient in proper biotin, physiological symptoms such as anemia, anorexia, vomiting, dermatitis, and hair loss can occur. Also if the livestock is lack of biotin, the livestock can develop slowly and grow slowly, and even die. Therefore, biotin is widely used as an additive in food, drink and animal feed.

The industrial research on d-biotin has never been stopped since the discovery of biotin. The d-biotin structure contains a five-carbon side chain, and how to efficiently introduce a pentanoic acid side chain from (3aS,6aR) thiolactone is the focus of attention of researchers at present. At present, the number of the introduced carbon chains can be divided into the following types: c3+ C2, C4+ C1, C5+ C0, C1+ C4 and C6-C1.

Goldberg and Sternbach et al (US2489236) first reported the introduction of a pentanoic acid side chain using the C3+ C2 strategy. Firstly, introducing a three-carbon side chain through a Grignard addition reaction of (3aS,6aR) thiolactone, then dehydrating, hydrogenating and carrying out acidic hydrolysis to generate a sulfonium salt, then carrying out nucleophilic substitution reaction with diethyl malonate, and hydrolyzing and decarboxylating to realize the introduction of a five-carbon side chain, wherein the formula is shown aS follows:

Chen Feng (Chen Feng et al, study on asymmetric total synthesis of d-biotin, Proc. Pharman, 1999(11):822-827) uses propargyl ether as starting material and exchanges with Grignard reagent to form alkynyl magnesium reagent. Then adding with (3aS,6aR) thiolactone, introducing a three-carbon side chain, forming a sulfonium salt through alkynyl reduction, dehydration, catalytic hydrogenation and hydrolysis, and finally condensing and decarboxylating with diethyl malonate to realize the introduction of a five-carbon side chain, wherein the formula is shown aS follows:

The patent (US 2489232) introduced a four carbon side chain by the grignard reaction of thiolactones and introduced a five carbon side chain by dehydration, catalytic hydrogenation, bromination, cyanation, hydrolysis as shown in the following formula:

The construction of the five carbon side chain is achieved in the literature (Journal of the Pharmaceutical Society of Japan,1968,88(8): 964-970) by the addition of 1, 4-dichlorobutane bis-Grignard reagent to thiolactone to introduce a four carbon side chain, followed by addition to carbon dichloride, as shown in the following formula:

In the literature (Advanced Synthesis & Catalysis,2005,347(4):549-554), an aldehyde group is introduced by the addition of methoxymethyl Grignard reagent and (3aS,6aR) thiolactone, and a five-carbon side chain is constructed by a witting reaction, aS shown in the following formula:

Chen Feng et al (Synthesis,2003 (14):2155-2160) used cyanozinc organic reagents to introduce five-carbon side chains by Fukuyama coupling reaction with (3aS,6aR) thiolactone, aS shown in the following formula:

Chen Feng et al (Synthesis,2000, (14):2004-2008) successfully realize the introduction of a valeric acid side chain by adopting a strategy of C6-C1, a ketal Grignard reagent and (3aS,6aR) thiolactone are subjected to Grignard reaction to introduce the side chain, ketene is obtained through deprotection and dehydration, and then five-carbon side chain preparation is completed through iodoform reaction and hydrogenation, which is shown aS the following formula:

In summary, the prior art mainly realizes the introduction of the biotin five-carbon side chain through Witting reaction, Grignard reaction and Fukuyama coupling reaction, but the reactions have the problems of high price of side chain reagents, harsh reaction conditions, complex operation, serious pollution, low yield, poor chemical selectivity and the like. Therefore, the method has extremely strong practical significance for finding a reagent which is cheap, easy to obtain, simple to operate and low in cost to realize the construction of the biotin valeric acid side chain.

Disclosure of Invention

The invention aims to provide a synthesis method of a biotin intermediate, wherein a valeric acid side chain is introduced through a simple Grignard addition reaction, and the method has the advantages of mild reaction conditions, simple and convenient operation and high yield, and is very suitable for industrial large-scale production.

In order to achieve the purpose, the invention adopts the following technical route:

a method of synthesizing a biotin intermediate, comprising: performing Grignard addition reaction on a compound shown in a formula (I) and a Norman's reagent, and performing catalytic oxidation on the obtained compound shown in a formula (II) under the action of nitric oxide and an oxidant to obtain a biotin intermediate shown in a formula (III), wherein the specific reaction formula is as follows:

The Normant's reagent is XMg (CH)₂)₅OMgCl, wherein X is halogen Cl, Br or I.

The method utilizes a Normant's reagent with a specific structure to carry out a Grignard addition reaction, namely, a five-carbon side chain is introduced to the C4 position of thiolactone through a one-step reaction, and then the biotin intermediate is prepared through simple oxidation.

Preferably, the Normant's reagent is ClMg (CH)₂)₅OMgCl。

The molar ratio of the compound shown in the formula (I) to the Normant's reagent is 1: 1.2 to 3.0, and more preferably 1: 1.8 to 2.2.

the oxynitride is any one or more of 2,2,6, 6-tetramethylpiperidine oxynitride (TEMPO), 2-oxy-2-azaadamantane (AZADO) and azabicyclo [ 3.3.1N-oxyl ] nonylmethoxy nitroxide (ABNO), and is preferably a mixture of TEMPO and ABNO.

The oxidant is NaClO or NaClO₂、Ca(ClO)₂、Ca(ClO₂)₂Or NaBrO, preferably NaClO and NaClO₂A mixture of (a).

the molar ratio of the compound shown in the formula (I), the oxynitride and the oxidant is 1: 0.01-0.15: 1-5, preferably 1: 0.06-0.08: 1 to 3.

The synthesis method of the biotin intermediate specifically comprises the following steps:

(1) Dissolving a compound shown as a formula (I) in an organic solvent A, dropwise adding a Normant's reagent at-10-70 ℃ for reacting for 5-15 h, and carrying out post-treatment to obtain a compound shown as a formula (II);

(2) Dissolving the compound shown in the formula (II) obtained in the step (1), an oxynitride and an oxidant in an organic solvent B, reacting for 4-10 h at 10-60 ℃, and performing post-treatment to obtain the biotin intermediate shown in the formula (III).

In the step (1), preferably, the Normant's reagent is dripped at the temperature of 10-15 ℃ for reaction for 5-15 h.

The organic solvent A is toluene, diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, and further preferably tetrahydrofuran. The volume dosage of the organic solvent A is 5-10 mL/g based on the mass of the compound shown in the formula (I).

In the step (2), preferably, the reaction is carried out for 4-10 hours at the temperature of 35-40 ℃.

The organic solvent B is dichloromethane, chloroform, toluene, acetonitrile or tetrahydrofuran, preferably tetrahydrofuran. The volume dosage of the organic solvent A is 3-10 mL/g based on the mass of the compound shown in the formula (I).

The reaction is carried out under the preferable parameter conditions, so that the reaction can be more sufficient, and the utilization rate of reaction raw materials and the yield of products can be further improved.

In the step (1), the post-treatment method comprises the following steps: after the reaction is finished, adding a saturated ammonium chloride solution into the obtained reaction solution for quenching, standing for layering, concentrating an organic phase, and purifying by a column to obtain the compound shown in the formula (II).

In the step (2), the post-treatment method comprises the following steps: and after the reaction is finished, adding saturated sodium bisulfite into the obtained reaction solution for quenching, standing for layering, concentrating an organic phase, and purifying by a column to obtain the biotin intermediate shown in the formula (III).

Compared with the prior art, the invention has the beneficial effects that:

The method has simple process route, adopts cheap and easily-obtained (3aS,6aR) -1, 3-dibenzyl tetrahydro-1 h-thieno [3,4-d ] imidazole-2, 4-diketone aS the starting raw material, and completes the introduction of a five-carbon side chain through Grignard addition and catalytic oxidation reaction to prepare the biotin intermediate, and has the advantages of mild reaction conditions, simple and convenient operation, high yield, good chemical selectivity, low production cost and the like. The biotin intermediate can be prepared by removing the dibenzyl group through one-step reaction, greatly simplifies the production process of biotin, is very suitable for industrial production, and has higher practical application value and social and economic benefits.

Detailed Description

The invention is further illustrated by the following examples, without restricting its scope.

(I) preparing (3aS,6aR) -1, 3-dibenzyl-4-hydroxy-4- (5-hydroxypentyl) tetrahydro-1H-thieno [3,4-d ] imidazol-2 (3H) -one shown aS a formula (II):