CN108558653A - The preparation method of Sai Lexipa intermediates and Sai Lexipa - Google Patents
The preparation method of Sai Lexipa intermediates and Sai Lexipa Download PDFInfo
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- CN108558653A CN108558653A CN201810467600.7A CN201810467600A CN108558653A CN 108558653 A CN108558653 A CN 108558653A CN 201810467600 A CN201810467600 A CN 201810467600A CN 108558653 A CN108558653 A CN 108558653A
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- sai lexipa
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- lexipa
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- intermediates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
-
- 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
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/20—Nitrogen atoms
Abstract
The invention discloses the preparation method of a kind of Sai Lexipa intermediates and Sai Lexipa, the intermediate is compoundAnd compound
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to the preparation side of a kind of Sai Lexipa intermediates and Sai Lexipa
Method.
Background technology
Sai Lexipa is pulmonary hypertension (PAH) the treatment new drug of Actelion biopharmaceutical companys of Switzerland research and development, as
The new oral Ip prostacyclin receptor stimulating agents of first synthesis, will have obtained FDA approvals in the end of the year 2015, just be used as pulmonary artery high
Pressure patient starts the popularization of the additive treatment after Primary Care, it is contemplated that the year two thousand twenty sales forecast is up to 600,000,000 dollars or more.
Pulmonary hypertension is a kind of chronic, pulmonary disease for gradually deteriorating, it is characterized in that abnormal high blood occurs in pulmonary artery
Pressure, can cause patient's daily routines tired out.Since blood more hardy can be transported to lung by heart, which can frequently result in
Fatefulue heart failure, patient premature death or may need lung transplantation.
Common Ip analogs are selectively low, poor to lung main artery diastole effect, and Sai Lexipa has height to Ip receptors
Selectivity, on it is similar with the diastole effect of lung parteriole on lung main artery, do not substituted by vascular endothelial cell and regenerated influence.Match
Le Xipa is with prostacyclin access with other as a kind of selectively oral Ip prostacyclin receptor stimulating agent drugs
Target spot, the drug that must suck or be injected intravenously administration are compared, more convenient when in use, and can relax vascular smooth muscle, are expanded
Blood vessel is opened, pulmonary artery pressure is reduced.
Sai Lexipa the entitled 2- of chemistry [4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos] butoxy } -
N- (mesyl) acetamide, structural formula are as follows：
Patent WO2017042828 discloses a kind of Sai Lexipa following preparation method,
In the method, using compound SP-3 as starting material, chemical combination is obtained through condensation reaction with the chloro- n-butyl alcohols of 4- first
Object SP-5, then compound SP-5 and 2- bromo-acetic acid tert-butyls compound SP-6 is obtained by the reaction, compound SP-6 is using hydrolysis
Compound SP-7 is obtained by the reaction, then compound SP-7 passes through obtains Sai Lexipa with the acylation reaction of Methanesulfonamide.The party
The shortcomings that method is that compound SP-3 just obtains target product by four-step reaction, and step is more, the total moles conversion of compound SP-3
Rate is low, and only 29.6%, and compound SP-3 is that price is most expensive in all reagents, so the route production cost is high, no
Rationally.
Invention content
For disadvantage existing in the prior art, the object of the present invention is to provide a kind of rational Sai Lexipa of technological design
Preparation method, this method can effectively reduce production cost.
In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is：
In a first aspect, the invention discloses a kind of structural formulas of Sai Lexipa intermediates 1, as follows：
Second aspect, the invention discloses the structural formulas of another Sai Lexipa intermediates 2, as follows：
The third aspect, the invention discloses a kind of synthetic routes of Sai Lexipa, as follows：
The preparation method of Sai Lexipa provided by the invention a kind of, includes the preparation of intermediate 1 and intermediate 2, specific to walk
It is rapid as follows：
Step 1, prepare compound SP-4：In the presence of sodium hydroxide hydrolysis is occurred into for compound SP-5, is changed
Close object SP-4；
Step 2, prepare compound SP-2：Compound SP-4 and Methanesulfonamide are occurred in the presence of condensing agent acylated anti-
It answers, obtains compound SP-2；
Step 3, Sai Lexipa is prepared：Compound SP-3 is dissolved in organic solvent, alkali and intermediate SP-2 is added, certain
At a temperature of SP, i.e. Sai Lexipa is obtained by the reaction.
In the step 1, solvent used in prepare compound SP-4 is the mixed of the mixture of methanol and water, ethyl alcohol and water
The ratio between the mole of one kind in conjunction object, SP-5 used and sodium hydroxide is SP-5：Sodium hydroxide=1:(1.2~2.0), institute
Reaction temperature is room temperature~80 DEG C, and the reaction time used is 1~12 hour.
In the step 2, the solvent used in prepare compound SP-2 is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, dichloro
One kind in methane, chloroform, toluene, ortho-xylene, meta-xylene, paraxylene, compound SP-4 used and methane
The ratio between mole of sulfonamide and condensing agent is SP-4：Methanesulfonamide：Condensing agent=1:(1.1~1.8):(1.05~1.5),
Condensing agent used is selected from N, N '-carbonyl dimidazoles, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, two
One kind in carbodicyclo hexylimide, I-hydroxybenzotriazole, reaction temperature used is the reflux temperature of room temperature~solvent, used
Reaction time be 1~12 hour.
In the step 3, prepares the solvent used in Sai Lexipa and be selected from n,N-Dimethylformamide, N, N- dimethyl second
One kind in amide, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), toluene, ortho-xylene, meta-xylene, paraxylene, it is used
Alkali is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, tetramethyl
One kind in ammonium hydroxide, tetramethylammonium hydroxide pentahydrate, the ratio between SP-3 used and the mole of alkali and SP-2 are SP-
3：Alkali：SP-2=1：(1.1~2)：(1~1.6), reaction temperature used are the reflux temperature of room temperature~solvent, and used is anti-
It is 2~24 hours between seasonable.
Beneficial effects of the present invention：The present invention passes through hydrolysis and acylation reaction system by starting material of cheap SP-5
It is standby to obtain SP-2, Sai Lexipa then is obtained through single step reaction with expensive SP-3 and SP-2 again, to substantially increase
The conversion ratio of SP-2, reduces production cost, to embody the method for the present invention reasonability more preferably than the prior art.
Way of example
Embodiment 1
Step 1：Prepare compound SP-4：
Compound SP-5 (23.8g, 100mmol) is added in ethyl alcohol (80ml), water (80ml) is added, is then added
Sodium hydroxide (4.8g, 120mmol) opens stirring, is heated to 50 DEG C, reacts 3 hours, and the reaction was complete for the board monitoring of TLC points, concentration
Most of ethyl alcohol is removed, dilute hydrochloric acid is added, adjusts pH=1, dichloromethane extraction is added, stands liquid separation, collects organic phase, is added
Anhydrous sodium sulfate is dried, and concentration obtains light yellow oil SP-4 (19.32g, yield 92%).
ESI/MS：M/z=211 (M+H)+.
1HNMR(400MHz,CDCl3)：δppm10.5(s,1H),4.32(s,2H),3.39(t,2H),3.32(t,2H),
1.77(m,2H),1.46(m,2H)。
Step 2：Prepare compound SP-2：
Compound SP-4 (19g, 90mmol) is added in dichloromethane (200ml), N, N '-carbonyl dimidazoles are added
(16g, 99mol) opens stirring, reacts at room temperature 1 hour, Methanesulfonamide (9.4g, 99mol) is dissolved in dichloromethane (50ml)
In be added dropwise to reaction system, drip off rear room temperature continue stirring 5 hours, the reaction was complete for the board monitoring of TLC points, be added dilute hydrochloric acid, extraction,
Stratification discards water layer, and anhydrous sodium sulfate drying, concentration is added in organic layer, and residue is beaten with methyl tertiary butyl ether(MTBE), is obtained
Off-white powder SP-2 (23.37, yield 90%).
ESI/MS：M/z=288 (M+H)+.
1HNMR(400MHz,CDCl3)：δppm8.4(s,1H),4.33(s,2H),3.40(t,2H),3.34(t,2H),
2.65(s,3H),1.78(m,2H),1.47(m,2H)。
Step 3：Prepare compound Sai Lexipa：
Compound SP-3 (20.4g, 70.6mmol) is added in n,N-Dimethylformamide (150ml), carbon is added
Sour potassium (9.74g, 70.6mmol) and SP-2 (23.3g, 81.2mmol) open stirring, are heated to 90 DEG C and react 6 hours, TLC points
The reaction was complete for board monitoring, and reaction solution is cooled to room temperature, and is poured into water, and solid, filtering is precipitated, and filter cake is washed with absolute ethyl alcohol, then
It is recrystallized with absolute ethyl alcohol, obtains white solid Sai Lexipa (31.1g, yield 88.9%)
ESI/MS：M/z=497 (M+H)+.
1HNMR(400MHz,DMSO-D6)：δppm8.00(s,1H),7.42(d,2H),7.33(d,2H),7.29-7.17
(m,6H),4.72(hept,1H),3.91(s,2H),3.55(t,2H),3.44-3.39(m,2H),3.25(s,3H),1.77-
1.64(m,4H),1.26(d,6H)。
It can be seen that in the preparation method of Sai Lexipa provided by the invention a kind of, the molar yield of SP-3 is
88.9%, it, can be big far above the molar yield of 29.6% SP-3 reported in the patent WO2017042828 of the prior art
It is big to reduce production cost.Therefore, the preparation method technique of Sai Lexipa of the invention is more reasonable, is suitble to industry's enlarging production.
Claims (6)
1. a kind of Sai Lexipa intermediates 1, which is characterized in that structural formula is shown below：
2. a kind of preparation method of Sai Lexipa intermediates 1 according to claim 1, which is characterized in that including walking as follows
Suddenly：In the presence of sodium hydroxide hydrolysis is occurred into for compound SP-5, obtains the Sai Lexipa of structure shown in compound SP-4
Intermediate 1；
3. a kind of Sai Lexipa intermediates 2, which is characterized in that structural formula is shown below：
4. a kind of preparation method of Sai Lexipa intermediates 1 according to claim 1, which is characterized in that including walking as follows
Suddenly：In the presence of condensing agent acylation reaction is occurred into for compound SP-4 and Methanesulfonamide, is obtained with shown in compound SP-2
The Sai Lexipa intermediates 2 of structure；
5. a kind of preparation method of Sai Lexipa, which is characterized in that include the following steps：
Compound SP-3 is dissolved in organic solvent, alkali and compound SP-2 is added, Sai Lexipa is obtained by the reaction at a certain temperature,
6. the preparation method of Sai Lexipa according to claim 5 a kind of, which is characterized in that the alkali is selected from hydroxide
Sodium, potassium hydroxide, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, tetramethylammonium hydroxide, tetramethyl
One kind in base ammonium hydroxide pentahydrate.
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| CN201810467600.7A CN108558653A (en) | 2018-05-14 | 2018-05-14 | The preparation method of Sai Lexipa intermediates and Sai Lexipa |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213343A (en) * | 2022-01-07 | 2022-03-22 | 江苏豪森药业集团有限公司 | Preparation and purification method of celecoxib intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1483033A (en) * | 2000-12-23 | 2004-03-17 | - | Tetrahydropyridine derivatives, their preparation and their use as cell proliferation inhibitors |
| CN1516690A (en) * | 2001-04-26 | 2004-07-28 | �ձ���ҩ��ʽ���� | Heterocyclic derivatives and medicines |
| CN105949135A (en) * | 2016-05-10 | 2016-09-21 | 湖南欧亚生物有限公司 | Synthetic method of selexipag |
-
2018
- 2018-05-14 CN CN201810467600.7A patent/CN108558653A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1483033A (en) * | 2000-12-23 | 2004-03-17 | - | Tetrahydropyridine derivatives, their preparation and their use as cell proliferation inhibitors |
| CN1516690A (en) * | 2001-04-26 | 2004-07-28 | �ձ���ҩ��ʽ���� | Heterocyclic derivatives and medicines |
| CN105949135A (en) * | 2016-05-10 | 2016-09-21 | 湖南欧亚生物有限公司 | Synthetic method of selexipag |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213343A (en) * | 2022-01-07 | 2022-03-22 | 江苏豪森药业集团有限公司 | Preparation and purification method of celecoxib intermediate |
| CN114213343B (en) * | 2022-01-07 | 2024-04-16 | 江苏豪森药业集团有限公司 | Preparation and purification methods of celecoxib intermediate |
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Application publication date: 20180921 |
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