阅读说明：本技术 一种(s)-3-吡咯烷醇盐酸盐的合成方法 (Synthesis method of (S) -3-pyrrolidinol hydrochloride ) 是由 张启龙 许坤 王红磊 高令峰 郑庚修 李学坤 于 2020-04-30 设计创作，主要内容包括：本发明公开了一种(S)-3-吡咯烷醇盐酸盐的合成方法,属于药物合成领域,该方法以L-苹果酸与苄胺为原料经过脱水酰胺化得到(3S)-N-苄基-3-羟基吡咯烷-2,5-二酮,之后一锅法还原、脱苄基,成盐合成(S)-3-吡咯烷醇盐酸盐。本发明合成路线短,操作简单,收率高,产品纯度好,利于工业化生产。(The invention discloses a synthesis method of (S) -3-pyrrolidinol hydrochloride, belonging to the field of drug synthesis, and the method comprises the steps of taking L-malic acid and benzylamine as raw materials, dehydrating and amidating to obtain (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone, reducing by a one-pot method, debenzylating, and salifying to synthesize the (S) -3-pyrrolidinol hydrochloride. The method has the advantages of short synthetic route, simple operation, high yield and good product purity, and is beneficial to industrial production.)

1. A synthetic method of (S) -3-pyrrolidinol hydrochloride comprises the following steps:

s1: dehydrating the L-malic acid and benzylamine to obtain (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone;

s2: reducing the (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone and salifying with hydrochloric acid to obtain (S) -3-pyrrolidinol hydrochloride.

2. The method for synthesizing (S) -3-pyrrolidinol hydrochloride according to claim 1, wherein said solvent in step S1 is one or more selected from toluene, xylene, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, and ethylene glycol monomethyl ether, and the amount of solvent is 5 times of the mass of L-malic acid; the reaction temperature is 100-110 ℃.

3. The method for synthesizing (S) -3-pyrrolidinol hydrochloride according to claim 1, wherein said molecular sieve in step S1 is one or more of 3A molecular sieve, 4A molecular sieve and 5A molecular sieve, and the addition amount is 1.3 times of the mass of L-malic acid.

4. The method for synthesizing (S) -3-pyrrolidinol hydrochloride according to claim 1, wherein said solvent in step S2 is ethanol, said reaction temperature is 70-80 deg.C, and said reaction pressure is 0.5-0.6 MPa.

5. The method for synthesizing (S) -3-pyrrolidinol hydrochloride according to claim 1, wherein said catalyst in step S2 is 10% palladium on carbon, and is added in an amount of 5% by mass of (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-dione.

Technical Field

The invention belongs to the field of drug synthesis, and relates to a synthesis method of (S) -3-pyrrolidinol hydrochloride.

Background

Larotrectinib (LOXO-101) is sold as Vitrakvi, and Chinese translation name is: erlotinib or erlotinib, which is an ATP-competitive, orally selective inhibitor, has a nanomolar 50% inhibitory concentration for three subtypes (TRKA, B and C) of tropomyosin-associated kinase (TRK) family of receptors. 11/27 of 2018, FDA accelerated approval for the co-developed pan-cancer-targeted drug vitrakvi (larotretinib) by Bayer and Loxo Oncology for marketing in adult and pediatric patients with locally advanced or metastatic solid tumors carrying NTRK gene fusion.

Ralotinib formula: c₂₁H₂₂F₂N₆O₂Molecular weight: 428.4, CAS: 1223403-58-4, chemical name: (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl]Pyrazolo [1,5-A]Pyrimidin-3-yl]-3-hydroxy-1-pyrrolidinecarboxamide, having the following chemical formula:

wherein (S) -3-pyrrolidinol is a key chiral intermediate for synthesizing ralotinib, and is also an important intermediate for synthesizing antihypertensive drugs barnidipine, drugs darifenacin for treating overactive bladder, asimadoline for treating irritable bowel syndrome, antiarrhythmic drugs vinacaran, and anticholinergic drugs glycopyrrolate. The chemical structural formula is as follows:

patent CN105646321A relates to a method for synthesizing (S) -3-pyrrolidinol, and the specific synthetic route is as follows:

the method comprises the following steps of firstly carrying out Mitsunobu reaction on (R) -1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine and carrying out acid condensation to obtain ester with reversed configuration, then hydrolyzing the ester under an alkaline condition to obtain (S) -1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine, and then removing a Boc protecting group under an acidic condition to finally obtain (S) -3-pyrrolidinol. The method is simple and easy to implement, low in cost and good in yield, and has potential production value, and raw materials are cheap and easy to obtain. The disadvantage is that the steps are long.

A method for synthesizing (S) -N-benzyl-3-hydroxypyrrolidine by using L-malic acid as a chiral raw material is reported in the literature (Liuqiang, Wusong. (S) -N-benzyl-3-hydroxypyrrolidine [ J ]. chemical reagent, 2010,32(9):843-844.), wherein the L-malic acid is reacted with acetyl chloride to generate (S) -2-acetyl malic anhydride, then cyclized with benzylamine, deacetylated by ester exchange reaction, recrystallized to purify a key intermediate, finally reduced by boron trifluoride-sodium borohydride, hydrogenated, reduced and debenzylated to obtain (S) -3-pyrrolidinol, and the total reaction yield is 59%. The yield is moderate, the method is simple and easy to implement, and the defect is long steps. The specific synthetic route is as follows:

literature (preparation of Liao cloud phoenix. 3- (S) - (-) - (1-carbamoyl-1, 1-benzhydryl) pyrrolidine tartrate [ J]Journal of the Chinese pharmaceutical industry 2011,42(5)) reports dehydration of L-malic acid and benzylamine at high temperature by NaBH₄/I₂Reducing amide, debenzylating palladium carbon to obtain (S) -3-pyrrolidinol, dehydrating xylene at 190 ℃, having high reaction temperature and certain potential safety hazard and adopting NaBH₄/I₂The yield of the reduced amide is 81 percent, but a large amount of iodine simple substance is consumed, the cost is increased, the recovery is difficult, and a large amount of waste water is generated and is difficult to treat. The specific synthetic route is as follows:

disclosure of Invention

Aiming at the defects in the prior art, the invention provides a synthesis method of (S) -3-pyrrolidinol hydrochloride.

The invention takes L-malic acid and benzylamine as raw materials, and obtains (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone through dehydration amidation, and then the (S) -3-pyrrolidinol hydrochloride is synthesized through one-pot reduction, debenzylation and salification, wherein the specific synthetic route is as follows:

s1: adding L-malic acid into methanol, stirring for dissolving, dropwise adding benzylamine at low temperature, stirring at room temperature for 3 hours after dropwise adding, concentrating the methanol, adding a solvent, adding a molecular sieve for dehydration, refluxing for 5-6 hours, performing heat filtration, recovering the molecular sieve, concentrating the filtrate to obtain a solid crude product, and recrystallizing the solid to obtain the (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-dione, wherein the yield is 85% and the purity is 98.5%.

S2: the method comprises the steps of reducing amido bond of (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone in a solvent at a certain temperature under a certain pressure under the catalysis of a catalyst by a one-pot method, removing benzyl to obtain (S) -3-pyrrolidinol, filtering and recovering palladium carbon, concentrating the solvent, adding isopropanol, stirring and dissolving completely, dropwise adding concentrated hydrochloric acid, stirring overnight at room temperature, and filtering to obtain a white solid, namely (S) -3-pyrrolidinol hydrochloride, wherein the yield is 88% and the purity is 99.2%.

In step S1, the solvent is one or more of toluene, xylene, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, and ethylene glycol monomethyl ether, preferably toluene, and the amount of the solvent is 5 times the mass of L-malic acid; the reaction temperature is 100-110 ℃; the molecular sieve is one or more of a 3A molecular sieve, a 4A molecular sieve and a 5A molecular sieve, preferably the 4A molecular sieve, and the adding amount is 1.3 times of the mass of the L-malic acid.

The solvent in the step S2 is ethanol, and the reaction temperature is 70-80 ℃, preferably 75 ℃; the reaction pressure is 0.5-0.6 MPa; the catalyst is 10% palladium carbon (water content is 58%, model D10H5A, New Material Co., Ltd., Shaanxi Rui) and the addition amount is 5% of the mass of (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone.

The invention has the beneficial effects that:

(1) short route, simple operation and high yield. According to the invention, cheap L-malic acid and benzylamine are selected as raw materials, and the (S) -3-pyrrolidinol can be obtained only by two-step reaction, and compared with the (3S) -N-benzyl-3-hydroxypyrrolidine-2, 5-diketone obtained in the prior art with the total yield of 60% in three steps, the product can be obtained with the yield of 85% in one step. (2) The reaction temperature is reduced, and the yield is improved. Compared with the existing high-temperature 190 ℃ dehydration process, the invention can complete the reaction only by 100-110 ℃ dehydration after adding the molecular sieve, and the yield is also improved to 88 percent from 76.3 percent in the existing process. (3) The invention adopts a palladium-carbon catalytic hydrogenation process to reduce amido bond by a one-pot method and simultaneously remove benzyl, thereby realizing the cleanness of the process and the high efficiency of functional group conversion.

Detailed Description