CN109942563A - A kind of preparation method of Su Woleisheng midbody compound - Google Patents
A kind of preparation method of Su Woleisheng midbody compound Download PDFInfo
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Abstract
The present invention relates to a kind of preparation methods of Su Woleisheng midbody compound.Specifically, the present invention provides a kind of preparation method of compound shown in Formulas I, the method includes the steps: in organic solvent, under the action of fatty acid and boron hydride, compound shown in Formula II reacts, to form compound shown in Formulas I.Method of the present invention avoids use that is expensive and being more toxic reagent, and sodium triacetoxy borohydride in the prior art is replaced with boron hydride, agents useful for same is economic and environment-friendly, significantly reduce cost, and it post-processes simply, product yield is higher, and chemical purity is greater than 99%, it can be smoothly used for the synthesis of Su Woleisheng, be suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, in particular it relates to a kind of system of Su Woleisheng midbody compound
Preparation Method.
Background technique
Su Woleisheng (English name: Suvorexant) chemical name are as follows:
[(7R) -4- (the chloro- 2- benzoxazolyl of 5-) hexahydro -7- methyl-1 H-1,4- diaza -1- base] [5- methyl -2-
(2H- triazole -2- base) phenyl] ketone, structural formula is as shown in following formula A: be MSD Corp., the U.S. exploitation a kind of orexin by
Body I (OX1R) and orexin receptor II (OX2R) inhibitor, clinically for treating insomnia.
A (Su Woleisheng)
During preparing Su Woleisheng, compound shown in the Formulas I of racemization is important intermediate, compound shown in Formulas I
Structural formula be the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles.Currently, through compound shown in Formula II
In the method for compound shown in preparation formula I, main synthetic method is as follows:
Method one: (US9108959B2 and Org.Process Res.Dev.2011,15,367-375)
In the route, compound shown in the Formulas I by reduction amination progress cyclization preparation racemization has been used expensive
Sodium triacetoxy borohydride, make that the production cost increases.Simultaneously because acetoxyl group is deposited in sodium triacetoxy borohydride
, therefore it is less economical to cause reaction of atomic.
Method two: (US9108959B2 and J.Am.Chem.Soc.2011,133,8362-8371)
Although the route is directly prepared for the R type optical isomer of compound shown in required Formulas I, reaction is logical
Cross the reductive amination process realization of metal Ru and chiral (S, S)-TIPSDPEN ligand participation.This method primary disadvantage is that with
Metal Ru and chiral ligand the two very expensive reagents, cost greatly increase, it is difficult to be suitble to industrialized production.
Method three: (WO2015008218A2)
In the route, anhydrous and oxygen-free, severe reaction conditions are needed, Cyanuric Chloride, which is more toxic and easily decomposes, is unfavorable for reaction
Implement, it is difficult to be suitble to industrialized production.
Although the prior art has been reported that several methods for preparing Su Woleisheng, they have one or more lack
Point such as uses expensive reagent (such as chiral ligand, ruthenium catalyst etc.), is more toxic reagent (Cyanuric Chloride), price is more expensive and former
Go back original reagent (sodium triacetoxy borohydride) of subeconomy difference etc..
Therefore, this field needs to develop a kind of simple, economical and can industrialize and give birth to a kind of synthesis Su Woleisheng's greatly
The method of midbody compound (compound shown in Formulas I).
Summary of the invention
Experiment purpose of the invention is to provide a kind of preparation method of Su Woleisheng midbody compound.
The first aspect of the present invention provides a kind of preparation method of compound shown in Formulas I, comprising steps of
In organic solvent, under the action of fatty acid and boron hydride, compound shown in Formula II reacts, from
And form compound shown in Formulas I:
In another preferred example, the boron hydride is selected from the group: sodium borohydride, potassium borohydride, or combinations thereof.
In another preferred example, the molar ratio of compound shown in the boron hydride and Formula II is 1-1.5:1.
In another preferred example, the fatty acid is C1~C4 saturated fatty acid.
In another preferred example, C1~C4 saturated fatty acid is selected from the group: formic acid, acetic acid, propionic acid, butyric acid, or
A combination thereof.
In another preferred example, C1~C4 saturated fatty acid is acetic acid.
In another preferred example, the molar ratio of the fatty acid and the boron hydride is 8-12:1.
In another preferred example, the organic solvent is selected from the group: methylene chloride, tetrahydrofuran, methyl tertiary butyl ether(MTBE),
Glycol dimethyl ether, methanol, ethyl alcohol, or combinations thereof.
In another preferred example, the organic solvent is methylene chloride.
In another preferred example, the volume mass ratio of the organic solvent and compound shown in Formula II is 1-10ml/g.
It in another preferred example, further include buffer salt in the system of the reaction.
In another preferred example, the buffer salt is selected from the group: sodium acetate, dipotassium hydrogen phosphate, disodium hydrogen phosphate or its
Combination.
In another preferred example, the buffer salt is selected as sodium acetate.
In another preferred example, the organic solvent is selected from the group: methylene chloride, ethyl alcohol, or combinations thereof；The rouge
Fat acid is acetic acid.
In another preferred example, the time of the reaction is 0.5-2 hours.
In another preferred example, the temperature of the reaction is -15 DEG C~15 DEG C.
In another preferred example, the temperature of the reaction is 5-10 DEG C.
In another preferred example, described to carry out post-processing purifying after reaction, the post-processing include extraction go out,
One of extraction, washing, dry, concentration, recrystallization are a variety of.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
The present inventor is by extensively and in-depth study, developing compound (a kind of synthesis Su Wolei shown in a kind of Formulas I
Raw midbody compound) preparation method, comprising steps of in organic solvent, in the effect of fatty acid and boron hydride
Under, compound shown in Formula II reacts, to form compound shown in Formulas I.It is high that method of the present invention avoids price
Use that is expensive and being more toxic reagent, agents useful for same is economic and environment-friendly, significantly reduces cost, and post-processes simple, product yield
Higher, chemical purity is greater than 99%, is suitable for industrialized production.Based on above-mentioned discovery, inventor completes the present invention.
Term
As used herein, the terms "include", "comprise" are used interchangeably with " containing ", not only include open definition, also
Including semi-enclosed and closed definition.In other words, the term include " by ... constitute ", " substantially by ... structure
At ".
The preparation method of compound shown in Formulas I
The present invention provides a kind of preparation methods of compound shown in Formulas I, comprising steps of
In organic solvent, under the action of fatty acid and boron hydride, compound shown in Formula II reacts, from
And form compound shown in Formulas I:
It should be understood that compound shown in Formula II of the present invention includes free form, salt form or free form
With the combination of salt form, the salt form can be the forms such as dimethanesulfonate (2MSA), a mesylate, hydrochloride, excellent
Select dimethanesulfonate form.
Under the conditions of using boron hydride, compound shown in Formula II reacts to form compound shown in Formulas I the present invention,
In a preferred embodiment of the present invention, the boron hydride is selected from the group: sodium borohydride, potassium borohydride, or combinations thereof.
In a preference of the invention, the molar ratio of compound shown in the boron hydride and Formula II is 1-1.5:
1。
In another preference of the invention, the fatty acid is C1~C4 saturated fatty acid.Preferably, described
C1~C4 saturated fatty acid is selected from the group: formic acid, acetic acid, propionic acid, butyric acid, or combinations thereof.It is highly preferred that C1~the C4 is full
It is acetic acid with fatty acid.
In another preferred example, the molar ratio of the fatty acid and the boron hydride is 8-12:1.
In a preference of the invention, the organic solvent is selected from the group: methylene chloride, tetrahydrofuran, methyl
Tertbutyl ether, glycol dimethyl ether, methanol, ethyl alcohol, or combinations thereof.Preferably, the organic solvent is preferably methylene chloride.
In another preferred example, the volume mass ratio of the organic solvent and compound shown in Formula II is 1-10ml/g.
It further include buffer salt in the system of the reaction in another preference of the invention.Preferably, described
Buffer salt is selected from the group: sodium acetate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or combinations thereof.It is highly preferred that the buffer salt selects
For sodium acetate.
In another preferred example, the organic solvent is selected from the group: methylene chloride, ethyl alcohol, or combinations thereof；The rouge
Fat acid is acetic acid.
In another preference of the invention, the temperature of the reduction reaction can be normal in the such reduction reaction in this field
Temperature, it is preferable that the temperature of the reaction is -15 DEG C -15 DEG C, preferable 5-10 DEG C.
In another preferred example, the time of the reduction reaction can be by conventional detection means detection reaction completion
Only, it is preferable that the time of the reaction is 0.5-2 hours.
In the present invention, each condition of the reaction all can be such also according to this field in addition to above-mentioned special instruction
Condition in original reaction carries out.
After above-mentioned reduction reaction, post-processing purifying can be carried out, the post-processing includes that extraction goes out, extracts, washing, doing
One of dry, concentration, recrystallization are a variety of.
R type chemical combination is made in the method that the compound I of racemization in the present invention can be split by D- (+)-dibenzoyl tartaric acid
Object I is used to prepare Su Woleisheng.
Main advantages of the present invention:
A kind of preparation method of compound shown in Formulas I of the present invention (midbody compound for synthesizing Su Woleisheng) is kept away
Exempt from expensive and be more toxic the use of reagent, and has replaced triacetoxy boron hydride in the prior art with boron hydride
Sodium, agents useful for same is economic and environment-friendly, significantly reduces cost, and post-process simply, product yield is higher, and chemical purity is greater than
99%, it can be smoothly used for the synthesis of Su Woleisheng, be suitable for industrialized production.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 60 DEG C, by sodium borohydride (29.93g, 791.97mmol) be added to several times acetic acid (475.18g,
In 7919.70mmol), 2500ml methylene chloride is added, is cooled to 10 DEG C, is added sodium acetate (43.29g, 527.98mmol),
Double mesylate compound II (250g, 527.98mmol) are added, are stirred to react 1h at 10 DEG C, then with 5mol/L hydroxide
Sodium solution tune pH=10, separates organic phase, and water phase uses 1200ml methylene chloride to extract twice again, merges during organic phase is washed to
Property, anhydrous sodium sulfate is dry to be concentrated to give solid 137.53g, and yield 98.11%, purity is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.12 (m, 2H), 6.92 (dd, J=8.2,1.8Hz, 1H), 3.97 (m, 3H), 3.65-3.55 (m, 3H), 3.40 (m,
1H), 2.24 (s, 1H), 2.11 (m, 1H), 1.41 (d, J=6.7Hz, 3H).
Embodiment 2
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 55 DEG C, by potassium borohydride (4.27g, 79.19mmol) be added to several times acetic acid (57.01g,
In 950.28mmol), 75ml methanol is added, is cooled to 5 DEG C, is added sodium acetate (4.32g, 52.79mmol), is added double
Mesylate compound II (25g, 52.79mmol) is stirred to react 2h at 10 DEG C, is 5mol/L sodium hydroxide solution tune with concentration
PH=10 is added 400ml methylene chloride and separates organic phase, and water phase uses 400ml methylene chloride to extract twice again, merges organic phase water
It is washed till neutrality, anhydrous sodium sulfate is dry to be concentrated to give solid 13.34g, and yield 95.20%, purity is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.11 (m, 2H), 6.91 (dd, J=8.2,1.8Hz, 1H), 3.96 (m, 3H), 3.65 (m, 3H), 3.38 (m, 1H), 2.24
(s, 1H), 2.11 (m, 1H), 1.41 (d, J=6.7 Hz, 3H).
Embodiment 3
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 60 DEG C, by sodium borohydride (1.43g, 38.01mmol) be added to several times propionic acid (28.13 g,
In 380.14mmol), 150ml tetrahydrofuran is added, is cooled to 5 DEG C, is added sodium acetate (2.59g, 31.67mmol), then plus
Enter hydrochloride compound II (15g, 31.67mmol), be stirred to react 1.5h at 10 DEG C, is that 5mol/L sodium hydroxide is molten with concentration
Liquid tune pH=10 is added isopropyl acetate 300ml and separates organic phase, and water phase is used 300ml isopropyl acetate to extract twice again, merged
Organic phase is washed to neutrality, and anhydrous sodium sulfate is dry to be concentrated to give solid 8.05g, and yield 95.77%, purity is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.08 (m, 2H), 6.93 (dd, J=8.2,1.8Hz, 1H), 3.99 (m, 3H), 3.65 (m, 3H), 3.37 (m, 1H), 2.24
(s, 1H), 2.06 (m, 1H), 1.40 (d, J=6.7 Hz, 3H).
Embodiment 4
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 60 DEG C, by sodium borohydride (0.83g, 21.96mmol) be added to several times butyric acid (21.26g,
In 241.60mmol), add 80ml methyl tertiary butyl ether(MTBE), be cooled to 10 DEG C, be added disodium hydrogen phosphate (2.39g,
16.89mmol), double mesylate compound II (8g, 16.89 mmol) are added, 1h is stirred to react at 10 DEG C, is with concentration
5mol/L sodium hydroxide solution tune pH=10, separates organic phase, and water phase is used 40ml methyl tertiary butyl ether(MTBE) to extract twice again, is associated with
Machine is mutually washed to neutrality, and anhydrous sodium sulfate is dry to be concentrated to give solid 4.15g, and yield 92.65%, purity is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.11 (m, 2H), 6.97 (dd, J=8.2,1.8Hz, 1H), 3.89 (m, 3H), 3.62 (m, 3H), 3.5 (m, 1H), 2.24
(s, 1H), 2.07 (m, 1H), 1.42 (d, J=6.7 Hz, 3H).
Embodiment 5
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 60 DEG C, by potassium borohydride (2.14g, 39.73mmol) be added to several times formic acid (16.44g,
In 357.54mmol), add 60ml glycol dimethyl ether, be cooled to 10 DEG C, be added dipotassium hydrogen phosphate (4.4g,
25.34mmol), it adds hydrochloride compound II (12g, 39.73mmol), is stirred to react 0.5h at 10 DEG C, is with concentration
5mol/L sodium hydroxide solution tune pH=10 is added 500ml methylene chloride, separates organic phase, water phase uses 500ml dichloromethane again
Alkane extracts twice, merges organic phase and is washed to neutrality, anhydrous sodium sulfate drying is concentrated to give solid 6.46g, and yield 96.11% is pure
Degree is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.12 (m, 2H), 6.94 (dd, J=8.2,1.8Hz, 1H), 3.88 (m, 3H), 3.62 (m, 3H), 3.37 (m, 1H), 2.24
(s, 1H), 2.06 (m, 1H), 1.41 (d, J=6.7 Hz, 3H).
Embodiment 6
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 60 DEG C, by sodium borohydride (11.97g, 316.78mmol) be added to several times acetic acid (190.07g,
In 3167.89mmol), 150ml methylene chloride is added, is cooled to 10 DEG C, is added sodium acetate (25.97g, 316.78mmol),
Double mesylate compound II (150g, 316.78mmol) are added, 1h is stirred to react at 10 DEG C, is 5mol/L hydrogen with concentration
Sodium hydroxide solution tune pH=10, separates organic phase, and water phase uses 75ml methylene chloride to extract twice again, merges during organic phase is washed to
Property, anhydrous sodium sulfate is dry to be concentrated to give solid 82.84g, and yield 98.50%, purity is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.11 (m, 2H), 6.92 (dd, J=8.2,1.8Hz, 1H), 3.93 (m, 3H), 3.64 (m, 3H), 3.35 (m, 1H), 2.24
(s, 1H), 2.08 (m, 1H), 1.41 (d, J=6.7 Hz, 3H).
Embodiment 7
The preparation of the chloro- 2- of 5- (5- methyl-[1,4] diazacyclo hept- 1- yl)-benzoxazoles (compound shown in Formulas I)
Lower than at 60 DEG C, by sodium borohydride (1.48g, 39.31mmol) be added to several times acetic acid (23.6g,
In 393.18mmol), 75ml ethyl alcohol is added, is cooled to 10 DEG C, is added sodium acetate (3.22g, 39.31 mmol), adds trip
Amorph compound II (15g, 39.31mmol) is stirred to react 1h at 10 DEG C, is 5mol/L sodium hydroxide solution tune pH=with concentration
10,400ml methylene chloride is added and separates organic phase, water phase uses 400ml methylene chloride to extract twice again, merges organic phase and is washed to
Neutrality, anhydrous sodium sulfate is dry to be concentrated to give solid 10.28g, and yield 98.50%, purity is greater than 99%.
MS (ES+): m/z 266.1 (M+H)；It can be seen that 265.9,267.9 (30%) peaks；1H NMR(500MHz, CD3OD):
δ=7.10 (m, 2H), 6.97 (dd, J=8.2,1.8Hz, 1H), 3.90 (m, 3H), 3.64 (m, 3H), 3.37 (m, 1H), 2.23
(s, 1H), 2.11 (m, 1H), 1.41 (d, J=6.7 Hz, 3H).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of preparation method of compound shown in Formulas I, which is characterized in that comprising steps of
In organic solvent, under the action of fatty acid and boron hydride, compound shown in Formula II reacts, thus shape
At compound shown in Formulas I:
2. method as shown in claim 1, which is characterized in that the boron hydride is selected from the group: sodium borohydride, hydroboration
Potassium, or combinations thereof.
3. method as shown in claim 1, which is characterized in that the molar ratio of compound shown in the boron hydride and Formula II
For 1-1.5:1.
4. method as shown in claim 1, which is characterized in that the fatty acid is C1~C4 saturated fatty acid.
5. method as shown in claim 1, which is characterized in that the molar ratio of the fatty acid and the boron hydride is 8-
12:1。
6. method as shown in claim 1, which is characterized in that the organic solvent is selected from the group: methylene chloride, tetrahydro furan
It mutters, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, methanol, ethyl alcohol, or combinations thereof.
7. method as shown in claim 1, which is characterized in that the volume mass of compound shown in the organic solvent and Formula II
Than for 1-10ml/g.
8. the method as described in claim 1, which is characterized in that further include buffer salt in the system of the reaction.
9. the method as described in claim 1, which is characterized in that the organic solvent is selected from the group: methylene chloride, ethyl alcohol,
Or combinations thereof；The fatty acid is acetic acid.
10. the method as described in claim 1, which is characterized in that the time of the reaction is 0.5-2 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101627028A (en) * | 2006-12-01 | 2010-01-13 | 默克公司 | Substituted diazepan compounds as orexin receptor antagonists |
| WO2015008218A2 (en) * | 2013-07-15 | 2015-01-22 | Dr. Reddy’S Laboratories Limited | Process for the preparation of suvorexant and intermediates useful in the synthesis of suvorexant |
| US9108959B2 (en) * | 2011-03-03 | 2015-08-18 | Merck Sharp & Dohme Corp. | Process for the preparation of an orexin receptor antagonist |
| CN106866632A (en) * | 2017-01-19 | 2017-06-20 | 成都美域高制药有限公司 | A kind of method for preparing Suvorexant intermediates and the like |
| CN107021955A (en) * | 2016-02-01 | 2017-08-08 | 上海奥博生物医药技术有限公司 | Su Woleisheng midbody compounds and preparation method thereof |
-
2017
- 2017-12-21 CN CN201711394464.5A patent/CN109942563A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101627028A (en) * | 2006-12-01 | 2010-01-13 | 默克公司 | Substituted diazepan compounds as orexin receptor antagonists |
| US9108959B2 (en) * | 2011-03-03 | 2015-08-18 | Merck Sharp & Dohme Corp. | Process for the preparation of an orexin receptor antagonist |
| WO2015008218A2 (en) * | 2013-07-15 | 2015-01-22 | Dr. Reddy’S Laboratories Limited | Process for the preparation of suvorexant and intermediates useful in the synthesis of suvorexant |
| CN107021955A (en) * | 2016-02-01 | 2017-08-08 | 上海奥博生物医药技术有限公司 | Su Woleisheng midbody compounds and preparation method thereof |
| CN106866632A (en) * | 2017-01-19 | 2017-06-20 | 成都美域高制药有限公司 | A kind of method for preparing Suvorexant intermediates and the like |
Non-Patent Citations (3)
| Title |
|---|
| CARL A. BAXTER ET AL.: "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder", 《ORG. PROCESS RES. DEV》 * |
| 梯泽等: "《当代有机反应和合成操作（第二版）》", 30 November 2017, 华东理工大学出版社 * |
| 相延英等: "苏沃雷生合成路线图解", 《中国医药工业杂志》 * |
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