阅读说明：本技术 一种（r）-3-氨基丁醇的合成方法 (Synthesis method of (R) -3-aminobutanol ) 是由 周魏魏 黄露祺 李明霞 贺志良 繆炳林 李进祥 曹俊爽 于 2019-08-22 设计创作，主要内容包括：本发明属于医药化工领域,具体涉及一种手性药物中间体(R)-3-氨基丁醇的制备方法。本发明采用(R)-3-氨基丁酸为原料,经酯化、氨基保护、还原、脱保护四个基本步骤得到了化学纯度和光学纯度都很好的产品。本发明采用的原料易得,价格便宜,相较于现有的化学拆分和手性引入,大幅提高了收率,降低了成本,而且易于实现规模化生产,是一种安全风险小,具有较高优势的合成方法。(The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a chiral drug intermediate (R) -3-aminobutanol. The invention adopts (R) -3-aminobutyric acid as raw material, and obtains the product with good chemical purity and optical purity through four basic steps of esterification, amino protection, reduction and deprotection. The method has the advantages of easily obtained raw materials, low price, greatly improved yield, reduced cost and easy realization of large-scale production compared with the existing chemical resolution and chiral introduction, and is a synthetic method with low safety risk and higher advantages.)

1. A preparation method of (R) -3-aminobutanol comprises the following steps:

1) taking (R) -3-aminobutyric acid as a raw material, and obtaining (R) -3-aminobutyric acid ester in an alcohol solvent under an acidic condition;

2) taking (R) -3-aminobutyric acid ester as a raw material, and reacting the raw material with an amino protecting group under an alkaline condition to obtain amino-protected (R) -3-aminobutyric acid ester;

3) taking amino-protected (R) -3-aminobutyric acid ester as a raw material, and carrying out reduction reaction with borohydride in an alcohol solvent in the presence of Lewis acid to obtain amino-protected (R) -3-aminobutanol;

4) taking (R) -3-aminobutanol protected by amino as a raw material, and directly removing the amino protecting group to obtain the (R) -3-aminobutanol.

2. The method of claim 1, wherein: the alcohol solvent in the step 1) is one or a mixture of more than two of linear chain or branched chain alcohols of C1-C7.

3. The method of claim 1, wherein: the acidic condition in the step 1) is a thionyl chloride, oxalyl chloride or sulfuric acid system.

4. The method of claim 1, wherein: the alkaline condition in the step 2) is sodium carbonate, triethylamine or sodium hydroxide.

5. The method of claim 1, wherein: the amino protecting group in the step 2) is acetyl chloride, benzyl chloroformate or benzoyl chloride.

6. The method of claim 1, wherein: the alcohol solvent in the step 3) is methanol, ethanol or isopropanol.

7. The method of claim 1, wherein: the Lewis acid in the step 3) is magnesium chloride, lithium chloride or calcium chloride.

8. The method of claim 1, wherein: the borohydride in the step 3) is potassium borohydride, sodium borohydride or lithium borohydride.

9. The method of claim 1, wherein: the deamination protection in the step 4) refers to the removal of amino protecting groups by direct hydrolysis or hydrogenation reduction under strong alkali conditions.

10. The method of claim 9, wherein: the deamination protection in the step 4) refers to catalytic hydrogenation of deamination protecting group under Pd/C.

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a chiral drug intermediate (R) -3-aminobutanol.

Background

(R) -3-aminobutanol, (R) -3-amino-1-butanol, CAS: 61477-40-5, colorless or light yellow liquid, is easily dissolved in tetrahydrofuran, ethanol, water and other solvents, and is a key intermediate of many chiral drugs. Chem.,1977,42:1650, which is reported to be a key intermediate of the antitumor drug 4-methylcyclophosphoramide; tetrahedr et al, lett, 1988,29:231, which is reported to be an important intermediate in the synthesis of penem antibiotics; drugs of the Future 2012,37:697, which is reported to be a key intermediate for the synthesis of the chiral six-membered ring of the anti-aids drug duruevir.

The structural formula of the (R) -3-aminobutanol is shown as the following formula (A):

the synthesis of (R) -3-aminobutanol has been reported in many patents, such as J.org.chem.1977,42:1650-1652, which describes the synthesis of chiral compounds by inducing the addition of chiral phenethylamine and crotonic acid ethyl ester, followed by reduction with lithium aluminum hydride to obtain protected amino alcohol, followed by palladium hydrogenation to obtain the desired product. Although the procedure is short, the process is not suitable for scale-up production, the reaction Scheme is shown in Scheme 1.

Tetrahedr, Lett.,1992,33(20):2895-2898 reports that (R) -N-benzyl-2-phenylglycine and acetaldehyde are reacted, and then subjected to ring opening, palladium-carbon hydrogenation and lithium aluminum hydride reduction to synthesize a target product. The ee value of the product in the route is only 60 percent and is far lower than the quality standard; the reaction Scheme is shown in Scheme 2.

U.S. 2003/73723 reports the reaction of tert-butyl crotonate with (R) -N-benzyl-1-phenylethylamine, the removal of hydrogen at-78 ℃ with strong base, the reduction with lithium aluminum hydride and the hydrogenation with a catalyst to obtain the target product. The route has higher safety risk, low product yield, high purification difficulty and unsuitability for scale-up production, and the reaction route is shown in Scheme 3.

Tetrahedron,2005,61(38): 9031-. The method has long steps, expensive raw materials and difficult processing of hydrolysis product lactone, is not suitable for scale-up production, and has a reaction route shown in Scheme 4.

US2011/0275855 reports that racemic 3-aminobutanol is resolved by (S) -mandelic acid to form (R) -3-aminobutanol mandelate, which is dissolved in morpholine and then distilled to obtain the final product, but the distilled product always contains a solvent which cannot be purified, the product purity is limited, and the reaction route is shown in Scheme 5.

Heterocyclic Lett, 2015,5(2):241-244 reports resolution of racemic 3-aminobutanol with (D) -tartaric acid to form (R) -3-aminobutanol tartrate, which is then dissociated with a base and extracted with acetonitrile to obtain the product. However, (R) -3-aminobutanol has high water solubility, the method has high post-treatment loss, and the scale-up production cannot be carried out, and the reaction route is shown in Scheme 6.

Disclosure of Invention

The invention provides a preparation method of (R) -3-aminobutanol, which has the advantages of cheap and easily obtained raw materials, simple process route, simple and rapid operation, greatly improved yield, reduced cost, less three wastes and easy realization of large-scale production compared with the existing chemical resolution and chiral introduction, and is a synthesis method with low safety risk and higher advantages.

The invention provides a preparation method of (R) -3-aminobutanol, which comprises the following steps:

1) taking (R) -3-aminobutyric acid as a raw material, obtaining (R) -3-aminobutyric acid ester in an alcohol solvent under an acidic condition, see formula 1

2) Taking (R) -3-aminobutyric acid ester as a raw material, and dropwise adding an amino protecting group under an alkaline condition to obtain the amino-protected (R) -3-aminobutyric acid ester shown in a formula 2.

3) Taking amino-protected (R) -3-aminobutyric acid ester as a raw material, and carrying out reduction reaction with borohydride in an alcohol solvent in the presence of Lewis acid to obtain amino-protected (R) -3-aminobutanol, which is shown in a formula 3.

4) Taking (R) -3-aminobutanol protected by amino as a raw material, and directly removing the amino protecting group to obtain the (R) -3-aminobutanol shown as a formula 4.

Preferably, the alcoholic solvent in step 1) is one or a mixture of more than two of linear or branched alcohols with C1-C7, preferably methanol, ethanol or isopropanol;

preferably, the acidic condition in step 1) is thionyl chloride, oxalyl chloride or sulfuric acid system;

preferably, the alkaline condition in step 2) is sodium carbonate, triethylamine or sodium hydroxide;

preferably, the amino protecting group in step 2) is acetyl chloride, benzyl chloroformate or benzoyl chloride;

preferably, the alcohol solvent in step 3) is methanol, ethanol or isopropanol;

preferably, the lewis acid of step 3) is any of the lewis acids conventionally used in such reactions, preferably magnesium chloride, lithium chloride or calcium chloride.

Preferably, the borohydride compound in step 3) is any conventional borohydride compound in such reactions, preferably potassium borohydride, sodium borohydride or lithium borohydride.

Preferably, the deamination protection in step 4) refers to the removal of an amino protecting group by direct hydrolysis or hydrogenation reduction under strong alkaline conditions.

The method adopts (R) -3-aminobutyric acid as a raw material for the first time, and sequentially carries out esterification, amino protection, reduction and deamination protecting group to obtain the (R) -3-aminobutanol with high optical purity; compared with the prior art, the method has the following advantages:

1) the invention has the advantages of easily obtained raw materials, low price and low cost;

2) the method has mild reaction conditions in each step, greatly improves the yield and reduces the production cost compared with the existing chemical resolution and chiral introduction;

3) the invention has high overall yield, no racemization is generated in the preparation process, and the chemical purity and the optical purity of the product (R) -3-aminobutanol are up to more than 99 percent.

Drawings

FIG. 1 is an H-NMR spectrum of methyl (R) -3-benzyloxyamidobutyrate.

FIG. 2 is an H-NMR spectrum of (R) -3-benzyloxyamidobutanol.

FIG. 3 is a typical spectrum of chemical purity GC detection of (R) -3-aminobutanol prepared by the method of the present invention.

FIG. 4 is a typical spectrum of chiral pure HPLC detection of (R) -3-aminobutanol prepared by the method of the present invention.

Detailed Description