CN113754623A - Preparation method of treprostinil intermediate - Google Patents

Preparation method of treprostinil intermediate Download PDF

Info

Publication number
CN113754623A
CN113754623A CN202111191864.2A CN202111191864A CN113754623A CN 113754623 A CN113754623 A CN 113754623A CN 202111191864 A CN202111191864 A CN 202111191864A CN 113754623 A CN113754623 A CN 113754623A
Authority
CN
China
Prior art keywords
formula
compound
substituted
base
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202111191864.2A
Other languages
Chinese (zh)
Inventor
胡杨
杨君
张晴晴
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Jinghe Pharmaceutical Technology Co ltd
Original Assignee
Shanghai Jinghe Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Jinghe Pharmaceutical Technology Co ltd filed Critical Shanghai Jinghe Pharmaceutical Technology Co ltd
Priority to CN202111191864.2A priority Critical patent/CN113754623A/en
Publication of CN113754623A publication Critical patent/CN113754623A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a preparation method for synthesizing treprostinil intermediate (I), which comprises the following steps: the compound of formula (II) or its carboxylate reacts with the compound of formula (III) in the presence of cyanuric chloride and alkali to directly obtain ketone compound (I). The process avoids environmental pollution caused by using heavy metal oxidant, simultaneously avoids adopting a low-temperature reaction method involving strong alkali, has mild reaction conditions, stable process, high purity of over 99 percent and wide industrial application prospect.

Description

Preparation method of treprostinil intermediate
Technical Field
The invention relates to a preparation method of a Treprostinil intermediate, belonging to the field of medicine synthesis.
Background
Pulmonary Arterial Hypertension (PAH) is a chronic and serious fatal disease called as malignant tumor in cardiovascular disease, which is clinically manifested by increased Pulmonary vascular resistance, increased Pulmonary arterial pressure, right heart failure, dyspnea, progressive dyspnea and movement obstruction, and ultimately death of right heart function due to exhaustion, and the treatment targets mainly include improvement of clinical symptoms of patients, enhancement of cardiac functional reserve of patients, and the like.
At present, no treatment method for effectively curing the PAH exists, the treatment of the PAH mainly adopts a traditional treatment method (comprising oxygen absorption, diuresis, cardiotonic and anticoagulation) before the first prostanoid medicine epoprostenol appears, and clinical symptoms are relieved through medicines so as to improve the quality of life and improve the survival rate. To date, treatment of PAH has been with calcium antagonists, prostacyclin analogues, endothelin receptor antagonists and 5-phosphodiesterase inhibitors. Among them, calcium antagonists have limited clinical use due to their risks of causing blood pressure lowering, worsening of heart failure, and inducing pulmonary edema. Indeed, calcium antagonists are only suitable for patients with PAH who are positive in the acute pulmonary vasodilation test. Epoprostenol, the first artificially synthesized prostacyclin drug, has been clinically proven to be effective in improving clinical symptoms and survival time of patients with pulmonary hypertension, and is considered to be the "gold standard" for treating pulmonary hypertension. However, the half-life of the drug in blood plasma is very short, only 3-5 minutes, and the drug cannot be orally taken, so continuous infusion through central veins is required, and the drug administration method has a plurality of defects, which also promotes the development and research of substitutes of the drug.
On 20/12/2014, treprostinil oral dosage form developed by United states FDA approved combination therapy (United Therapeutics): treprostinil diethanolamine sustained-Release Tablets (Treprostinil Extended-Release Tablets) are used for treating Pulmonary Arterial Hypertension (PAH). Treprostinil, as a first-batch medicine encouraging imitation of pharmaceuticals, is an artificially synthesized prostacyclin medicine, has stable physical properties and similar pharmacological action to endogenous PGI2, can expand pulmonary arteries by promoting cAMP expression in vascular endothelial cells, inhibiting growth of vascular smooth muscle cells and platelet aggregation, reduce excessive proliferation of the pulmonary vascular smooth muscle cells, prevent in-situ thrombosis in pulmonary arterioles, further reduce pulmonary artery pressure and pulmonary vascular resistance, increase cardiac output, improve blood oxygen saturation, and remarkably improve or even almost eliminate clinical symptoms, and is widely applied as a first-line treatment and rescue medicine.
Figure BDA0003301466780000021
Treprostinil was developed by United states pharmaceutical industries (United Therapeutics) and its compound patent US4306075A has expired. US patents US7417070, US7384978, US7544713 and US20070078095, US20050282901, US20080249167 disclose oral formulations of treprostinil and other prostacyclin analogues and their use for the treatment of various conditions.
It is known that treprostinil molecules have a fused ring structure and have multiple chiral centers, and thus the synthesis process is complicated. Aristoff et al first reported a method for preparing treprostinil (Tetrahedron Lett.1982,23,2067-2070), in which five-membered rings are synthesized by multi-step reactions, then aromatic rings are introduced by 1, 4-addition reaction, intermediate six-membered rings are constructed by ring closure by Friedel-Crafts reaction after olefination of carbonyl groups and asymmetric reduction, thereby obtaining a mother nucleus structure of treprostinil, and finally treprostinil is synthesized by multi-step reactions.
The chiral synthetic route needs 36 steps of reaction, and the steps are long, so that the method is not favorable for large-scale synthesis.
Figure BDA0003301466780000022
In 1999, United Therapeutics, WO9921830a1, disclosed a method for preparing treprostinil comprising the steps of:
Figure BDA0003301466780000031
the journal J.org.chem.2004,69,1890-1902 optimizes the preparation process reported in WO9921830A1 and reports the preparation of the side-chain compound 6:
Figure BDA0003301466780000032
the synthesis strategy is to synthesize a key intermediate 8 by taking m-methoxyphenol as a raw material through the key steps of claisen rearrangement, oxidation, nucleophilic addition of a side chain and the like. The treprostinil is synthesized by constructing a framework structure of treprostinil through asymmetric reduction and Pauson-Khand cyclization reaction, removing a chiral control group through hydrogenation reduction, reducing sodium borohydride, removing protection and the like. Compared with the prior reported route, the chiral synthetic route has obvious improvement on the synthetic efficiency and chiral control. There are still some drawbacks: excessive expensive chiral CBS reagent, cobaltic octacarbonyl and trimethylsilylpropyne are needed, so that the synthesis cost is high; the Claisen rearrangement reaction is a high-temperature reaction, the production safety coefficient is low, ortho-position isomer impurities are easy to generate, and the purification difficulty is high; the use of heavy metal oxidants easily causes the heavy metals of the product to exceed the standard; the step of side chain grafting is low-temperature reaction, the conditions are harsh, the production cost is high, and the industrial application value is low.
Disclosure of Invention
In order to solve the problems in the prior art, the inventor develops a preparation method of the treprostinil intermediate (I), the method has mild reaction conditions and relatively low cost, and the obtained product has the purity of more than 99 percent and is suitable for industrial production.
Figure BDA0003301466780000041
The invention aims to provide a preparation method of a treprostinil intermediate (I), which comprises the following steps:
reacting a compound of formula (II) or a carboxylate thereof with a compound of formula (III) to provide a compound of formula (I) having the formula:
Figure BDA0003301466780000042
wherein R is1，R2Each independently is a hydroxy protecting group; preferably R1、R2Each independently is substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl, benzyl, C1-6 alkoxy-substituted benzyl, tetrahydropyranyl, -SiR1R2R3Wherein R is1、R2And R3Each independently is C1-6 alkyl, C3-6 cycloalkyl or substituted or unsubstituted C6-10 aryl.
As a still further preferred embodiment, R1Is methyl, R2Is 2-tetrahydropyranyl.
As a still further preferred embodiment, the carboxylate salt of the compound of formula (II) is selected from sodium salts.
Preferably, the base is an organic base or an inorganic base, and the organic base is selected from triethylamine, N-diisopropylethylamine, pyridine, DBU, DABCO, DMAP or a mixture thereof; the inorganic base is selected from sodium carbonate, potassium carbonate or their mixture.
Further, the compound of formula (II) can be prepared by the following preparation method:
Figure BDA0003301466780000043
wherein R is1As defined in claim 1, R1Selected from substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl, benzyl, C1-6 alkoxy substituted benzyl, tetrahydropyranyl, -SiR1R2R3Wherein R is1、R2And R3Are respectively C1-6 alkyl, C3-6 cycloalkyl, or substituted or unsubstituted C6-10 aryl; wherein X is halogen, preferably bromine.
Further, the compound of formula (V) can be prepared by the following preparation method:
Figure BDA0003301466780000051
wherein R is1The base as defined in claim 1, wherein said base is lithium tetramethylpiperidine.
Further, the compound of formula (IV) can be prepared by the following preparation method:
Figure BDA0003301466780000052
wherein R is1The base as defined in claim 1 is an organic base selected from triethylamine, pyridine, morpholine, piperidine, DMAP or mixtures thereof or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate or mixtures thereof.
Further, the compound of formula (III) can be prepared by the following preparation method: prepared from a compound of formula (VIII) after hydroxy protection:
Figure BDA0003301466780000053
wherein R is2As defined in claim 1, R2Selected from substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl, benzyl, C1-6 alkoxy substituted benzyl, tetrahydropyranyl, -SiR1R2R3Wherein R is1、R2And R3Each independently is C1-6 alkyl, C3-6 cycloalkyl or substituted or unsubstituted C6-10 aryl.
Further, the compound of formula (VIII) can be prepared by the following preparation method: prepared by reacting a compound of formula (VII):
Figure BDA0003301466780000054
wherein X is halogen, preferably chlorine.
Further, the compound of formula (VII) can be prepared by the following preparation method: the compound of formula (VII) is prepared by taking (R) -glycidol as a raw material, and the preparation method is as follows:
Figure BDA0003301466780000061
in another aspect, the present invention provides a method for preparing a compound of formula (II) from m-hydroxybenzoic acid, comprising the steps of:
Figure BDA0003301466780000062
wherein R is1As defined for the compounds of formula (I).
As a priority scheme, when R1When X is selected from bromine, the specific preparation method is as follows:
Figure BDA0003301466780000063
in another aspect, the present invention provides a method for preparing a compound of formula (III) from (R) -glycidol, comprising the steps of:
Figure BDA0003301466780000064
wherein R is2As defined for the compounds of formula (I).
As a priority scheme, when R2When the compound is selected from 2-tetrahydropyranyl and X is selected from chlorine, the specific preparation method is as follows:
Figure BDA0003301466780000071
compared with the prior art, the invention has the following advantages: the treprostinil intermediate (I) provided by the invention can be obtained by reacting the compound of the formula (II) and the compound of the formula (III) at room temperature under the action of cyanuric chloride and alkali, the reaction condition is mild, the purity of the intermediate (I) is up to more than 99%, and oxidation and low-temperature reaction are avoided, so that the environmental pollution caused by using heavy metal (PCC oxidant) in the prior art is avoided, and the production operation is simplified. The method takes m-hydroxybenzoic acid as a raw material to synthesize the compound of the formula (II) in three steps, has mild reaction conditions, does not generate isomer by-products, avoids high-temperature reaction conditions and complex purification operation required by the Claisen rearrangement reaction reported in the prior art, and greatly improves the production cost and the safety coefficient. The method takes (R) -glycidol as a raw material to synthesize the compound of the formula (VII) in three steps, avoids using expensive trimethyl silicon propyne in the prior art, avoids low-temperature reaction of butyl lithium, simplifies the synthesis operation, and has low production cost and wide industrial application prospect.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100ml solution.
The terms used in the present invention have the following meanings, unless otherwise stated:
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 6 carbon atoms, preferably 5-or 6-membered cycloalkyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
"aryl" refers to a 6 to 10 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably phenyl and naphthyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Figure BDA0003301466780000081
M-hydroxybenzoic acid (96g, 0.7mol) and potassium carbonate (480g, 3.5mol) were placed in anhydrous acetone (1.2L), dimethyl sulfate (441g, 3.5mol) was added dropwise at room temperature, and after completion of the addition, the mixture was heated to 50 ℃ to react for 2 hours, and the reaction was stopped, followed by filtration, concentration of the filtrate under reduced pressure, addition of 20% aqueous NaOH (1.2L) to the residue, stirring until complete dissolution, cooling to 10 ℃, addition of concentrated brine to adjust pH to 2-3, filtration, washing of the filter cake with water (300mL), and recrystallization with ethanol to obtain m-methoxybenzoic acid (78g, 73.3% yield).
Example 2
Figure BDA0003301466780000091
Dissolving 2,2,6, 6-tetramethyl lithium piperidine (294g, 2.0mol) in tetrahydrofuran (200mL), reducing the temperature to 0 ℃, dropwise adding tetrahydrofuran (400mL) containing M-methoxybenzoic acid (80g, 0.53mol), reacting at 0 ℃ for 2 hours, adding iodine (380g, 1.5mol) in batches, heating to room temperature, continuing to stir for 12 hours, stopping the reaction, adding water (800mL), diluting, adjusting the pH to 2-3 with 1M HCl, adding ethyl acetate (400mL), extracting, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the obtained residue under reduced pressure, and crystallizing with acetone to obtain 2-iodine-3-methoxybenzoic acid (90.2g, yield 61.2%).
Example 3
Figure BDA0003301466780000092
Placing 2-iodine-3-methoxybenzoic acid (56g, 0.2mol) in tetrahydrofuran (500mL), cooling to-20 deg.C, adding dropwise methylmagnesium bromide (1M tetrahydrofuran solution) (200mL, 0.2mol), adding dropwise, continuing to add isopropylmagnesium chloride (2M tetrahydrofuran solution) (120mL, 0.24mol) dropwise, reacting at-20 deg.C for 2 hours, adding 3.3M tetrahydrofuran solution (3mL, 0.01mol) of cuprous cyanide bis (lithium chloride) complex, reacting at-20 deg.C for 1 hour, adding allyl bromide (72g, 0.6mol), stirring at room temperature for 12 hours, stopping reaction, adding ethyl acetate (500mL), diluting, adjusting pH to 2-3 with 1M HCl, standing for layering, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, dissolving the obtained residue with 100mL tetrahydrofuran, 10% NaOH aqueous solution was added dropwise to adjust pH to 8-9, and the mixture was filtered, and the filter cake was dried under vacuum to give sodium 2-allyl-3-methoxybenzoate (34.9g, yield 81.5%).
Example 4
Figure BDA0003301466780000093
Sodium 2-allyl-3-methoxybenzoate (21g, 0.1mol) was added to acetonitrile (120mL), cyanuric chloride (6.1g, 0.03mol) was added with stirring, and after stirring and reacting at room temperature for 0.5 hour, (6S) -6- ((tetrahydro-2H-pyranyl-2-yl) oxy) -dec-9-yne (23.8g, 0.1mol), triethylamine (10.1g, 0.1mol) and anhydrous magnesium chloride (9.5g, 0.1mol) were added, and after completion of addition, the reaction was continued at room temperature for 3 hours. The reaction mixture was filtered, the solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (300mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was flash eluted through a short silica gel column (n-hexane: ethyl acetate ═ 20:1) to give (6S) -1- (2-allyl-3- (methoxy) phenyl) -6- ((tetrahydro-2H-pyranyl-2-yl) oxy) -undecyl-2-yn-1-one (33.2g, yield 80.6%, HPLC purity 99.3%) as a yellow oil.
1H NMR(400MHz,CDCl3):δ7.72(t,J＝9.0Hz,1H),7.28(m,1H),7.05(d,J＝9.0Hz,1H),6.05-5.90(m,1H),5.01-4.88(m,2H),4.56-4.55(m,1H),3.91-3.78(m,4H),3.66-3.80(m,3H),3.51-3.43(m,1H),2.56(dt,J＝1.6,5.8Hz,1H),2.49(t,J＝5.9Hz,1H),1.90-1.22(m,16H),0.88(t,J＝6.9Hz,3H).
Example 5
Figure BDA0003301466780000101
Adding a mixture of magnesium chips (15g, 0.63mol), mercuric chloride (0.6g, 2.2mmol) and one iodine simple substance into anhydrous ether (150mL), dropwise adding propargyl bromide (5mL, 0.06mol) to initiate a reaction, cooling to 0-10 ℃, dropwise adding propargyl bromide (15mL, 0.18mol), and continuing stirring for reaction for 1 hour after dropwise adding, thereby obtaining the ether solution of propargyl magnesium bromide. Adding (R) -glycidol (5.9g, 0.08mol) into diethyl ether (30mL), cooling to-50 ℃, dropwise adding the propargyl magnesium bromide diethyl ether solution, naturally raising the temperature to room temperature after dropwise adding, continuously stirring for reaction for 15 hours, cooling to-10 ℃, dropwise adding saturated ammonium chloride aqueous solution (30mL) for quenching, filtering, standing the filtrate for demixing, extracting the aqueous phase with ethyl acetate (30mL), combining the organic phases, sequentially washing with water (30mL) and saturated NaCl aqueous solution (30mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain yellow oily matter, (8.8g) crude (8.8g) of (S) -hexadecane-5-alkyne-1, 2-diol, and directly using the crude product in the next reaction without further purification
Dissolving crude (S) -hexadecane-5-yne-1, 2-diol (8.8g) in dichloromethane (100mL), adding triethylamine (8.1g, 0.08mol), cooling to 0 ℃, adding p-toluenesulfonyl chloride (13.4g, 0.07mol) in portions, reacting at room temperature for 8 hours, adding water dropwise (50mL) and quenching, standing the filtrate for layering, extracting the aqueous phase with dichloromethane (50mL), combining the organic phases, washing with saturated aqueous NaCl solution (30mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a residue, and rapidly eluting through a short silica gel column (n-hexane: ethyl acetate ═ 100:1) to obtain yellow oily substance (S) -2-hydroxy-4-ethynyl-1-butyl p-toluenesulfonate (14.1g, yield 65.8%).
Example 6
Figure BDA0003301466780000102
Adding (S) -2-hydroxy-4-ethynyl-1-butyl-p-toluene sulfonate (10.7g, 0.04mol) and cuprous iodide (0.76g, 4mmol) into anhydrous tetrahydrofuran (120mL), cooling to 0 ℃, dropwise adding 2M tetrahydrofuran solution of n-butyl magnesium bromide (20mL, 0.04mol), stirring at 0 ℃ for 6 hours after dropwise adding, completely reacting, dropwise adding saturated aqueous ammonium chloride solution (30mL), quenching, filtering, standing the filtrate for layering, extracting the aqueous phase with ethyl acetate (50mL x 2), combining the organic phases, washing with water (30mL) and saturated aqueous NaCl solution (30mL) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain yellow oily matter (S) -oct-1-yn-5-ol (4.4g, 71.4% yield).
Example 7
Figure BDA0003301466780000111
(S) -oct-1-yn-5-ol (4.0g, 0.026mol) was added to dichloromethane (50mL), pyridine p-toluenesulfonate (PPTS) (0.33g, 1.3mmol) and 3, 4-dihydropyran (4.2g, 0.05mol) were added, and the mixture was stirred at room temperature for 15 h. The reaction was stopped, washed with water (20mL × 2) and then with saturated aqueous NaCl (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil, i.e., crude C-2 (94.7 g), which was separated and purified by silica gel column chromatography (n-hexane: ethyl acetate: 200:1) to give a pale yellow oil, i.e., (6S) -6- ((tetrahydro-2H-pyranyl-2-yl) oxy) -dec-9-yne (5.7g, yield 91.9%, GC purity: 98.6%).

Claims (10)

1. A process for the preparation of a compound of formula (I), comprising the steps of:
reacting a compound of formula (II) or a carboxylate thereof with a compound of formula (III) to provide a compound of formula (I) having the formula:
Figure FDA0003301466770000011
wherein R is1，R2Each independently is a hydroxy protecting group; preferably R1、R2Each independently is substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl, benzyl, C1-6 alkoxy-substituted benzyl, tetrahydropyranyl, -SiR3R4R5Wherein R is3、R4And R5Each independently is C1-6 alkyl, C3-6 cycloalkyl or substituted or unsubstituted C6-10 aryl.
2. The method of claim 1, wherein R is1Is methyl, R2Is 2-tetrahydropyranyl.
3. The process according to claim 1, wherein the carboxylate of the compound of formula (II) is selected from a lithium salt, a sodium salt or a potassium salt.
4. The method of claim 1, wherein the base is an organic base or an inorganic base, and the organic base is selected from triethylamine, N-diisopropylethylamine, pyridine, DBU, DABCO, DMAP or a mixture thereof; the inorganic base is selected from sodium carbonate, potassium carbonate or their mixture.
5. The process according to claim 1, wherein the compound of formula (II) is prepared as follows:
Figure FDA0003301466770000012
wherein R is1As defined in claim 1, R1Selected from substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl, benzyl, C1-6 alkoxy substituted benzyl, tetrahydropyranyl, -SiR1R2R3Wherein R is1、R2And R3Each independently is C1-6 alkyl, C3-6 cycloalkyl or substituted or unsubstituted C6-10 aryl; wherein X is halogen, preferably bromine.
6. The process according to claim 5, wherein the compound of formula (V) is prepared from a compound of formula (IV) by the action of iodine and a base,
Figure FDA0003301466770000021
wherein R is1The base as defined in claim 1, wherein said base is lithium tetramethylpiperidine.
7. The process according to claim 6, wherein the compound of formula (IV) is prepared from m-hydroxybenzoic acid under the action of a base,
Figure FDA0003301466770000022
wherein R is1The base as defined in claim 1 is an organic base selected from triethylamine, pyridine, morpholine, piperidine, DMAP or mixtures thereof or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate or mixtures thereof.
8. The method according to claim 1, wherein the compound of formula (III) is obtained by protecting a hydroxyl group in the compound of formula (VIII),
Figure FDA0003301466770000023
wherein R is2As defined in claim 1, R2Selected from substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl, benzyl, C1-6 alkoxy substituted benzyl, tetrahydropyranyl, -SiR1R2R3Wherein R is1、R2And R3Each independently is C1-6 alkyl, C3-6 cycloalkyl or substituted or unsubstituted C6-10 aryl.
9. The process according to claim 8, wherein the compound of formula (VIII) is obtained by reacting a compound of formula (VII) with an n-butyl magnesium halide,
Figure FDA0003301466770000024
wherein X is halogen, preferably chlorine.
10. The process according to claim 9, wherein the compound of formula (VII) is prepared starting from (R) -glycidol by the following steps:
Figure FDA0003301466770000025
。
CN202111191864.2A 2021-10-13 2021-10-13 Preparation method of treprostinil intermediate Pending CN113754623A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111191864.2A CN113754623A (en) 2021-10-13 2021-10-13 Preparation method of treprostinil intermediate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111191864.2A CN113754623A (en) 2021-10-13 2021-10-13 Preparation method of treprostinil intermediate

Publications (1)

Publication Number Publication Date
CN113754623A true CN113754623A (en) 2021-12-07

Family

ID=78799356

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111191864.2A Pending CN113754623A (en) 2021-10-13 2021-10-13 Preparation method of treprostinil intermediate

Country Status (1)

Country Link
CN (1) CN113754623A (en)

Similar Documents

Publication Publication Date Title
RU2388753C2 (en) Method of obtaining intermediate product taking part in irbesartan synthesis
CN101445457B (en) Isosteviol derivant and application thereof
CN103998423A (en) Process for the preparation of travoprost
CN116640088A (en) Preparation method of high-purity Lei Fen narasin
WO2010083722A1 (en) A process for one-pot synthesis of corey lactone
CN110746333B (en) Method for separating carboprost isomer
CN109734656B (en) Preparation method of nitrendipine
CN113754623A (en) Preparation method of treprostinil intermediate
KR101522218B1 (en) Processes and intermediates for the preparations of prostaglandins
CN103880801B (en) A kind of intermediate for preparing treprostinil that, its preparation method and the method that treprostinil that is prepared by it
CN107936045A (en) A kind of preparation method of high-purity Flurbiprofen known impurities
CN111362996A (en) Preparation method of gestodene impurity F
CN115785057B (en) Preparation method of ticagrelor intermediate compound and salt thereof
Bennett et al. Diastereoselective alkylation reactions of 1-methylcyclohexa-2, 5-diene-1-carboxylic acid
CN113416142B (en) Preparation method of 5-ALA intermediate 5-bromolevulinate
CN111440154B (en) Synthetic method of tegaserod dimer impurity
CN112624953B (en) Process for preparing biliverdin or its derivatives
CN112390816B (en) Preparation method of oxazepine compound
CN115819307B (en) Preparation method of prostaglandin E1
JP7273822B2 (en) Pyranose-substituted pyrazole compounds, methods of preparation and uses thereof
CN109942453A (en) A kind of new impurity and synthetic method of Valsartan
CN114671836A (en) Synthesis method of amiodarone impurity C
CN116813500A (en) Synthesis method of fluorodiclofenac and regorafenib
CN115160286A (en) Novel preparation process of rosuvastatin calcium intermediate
TW202327578A (en) Preparation method of aromatic ring derivative as immunomodulator

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination