CN106632121A - Method for preparing important Suvorexant intermediate - Google Patents
Method for preparing important Suvorexant intermediate Download PDFInfo
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- CN106632121A CN106632121A CN201510736723.2A CN201510736723A CN106632121A CN 106632121 A CN106632121 A CN 106632121A CN 201510736723 A CN201510736723 A CN 201510736723A CN 106632121 A CN106632121 A CN 106632121A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the technical field of medicines and relates to a method for preparing an important intermediate {2-[(5-chlorobenzoxazole-2-yl)-(3-one-butyl)-amino]ethyl}-tert-butyl carbamate. A highly toxic product methyl vinyl ketone is substituted by a compound with low toxicity, and due to catalytic reactions of DBU, LDA, NaHMDS, KHMDS and the like, a compound of a formula (3) can be obtained at high yield of 90% or higher. Moreover, the HPLC (high performance liquid chromatography) content of the crude product reaches 99.5% or higher, and the method disclosed by the invention is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of preparation method of important intermediate, and in particular to
The preparation of { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate
Method.
Background technology
Su Woleisheng (Suvorexant) is, by double orexin receptor antagonists of Merk companies newly research and development, to lead to
Crossing targeting blocking makes one the orexin that has difficulty in going to sleep and reaches the effect that helps patient to improve the health care of sleep.Complete at present
III phase clinical research, research finds that it can reduce the sleep starting-up time, improves patient sleeps' mass, side effect
It is few, it is suitable to long-term treatment.Su Woleisheng is expected to become the upper of the orexin receptor antagonists of first treatment insomnia
City's medicine, its structural formula is as follows：
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate is
Prepare the important intermediate of Su Woleisheng.Patent WO2012148553 reports { 2- [(5- chlorobenzene benzoxazoles
- 2 bases)-(3- ketone-butyl)-amino] ethyl-t-butyl carbamate synthetic method, its synthetic route is as follows：
The route has the disadvantage：(1) toxic articles ethylene methacrylic ketone is used in route, to eyes, skin and upper breathing
There are intense stimulus in road, and is difficult to buy and transports, therefore is unsuitable for industrialized production；(2) a pot of three-step reaction
Method is carried out, and intermediate is not separated, and is unfavorable for process control, difficult quality guarantee.
Patent WO2015008218 reports { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-ammonia
Base] ethyl-t-butyl carbamate synthetic method, its synthetic route is as follows：
The route has the disadvantage：(1) toxic articles ethylene methacrylic ketone is used in route, is unsuitable for industrialized production；(2)
Post processing is relatively complicated, needs multiple extracting operation, and yield is relatively low, and only 47.7%.
The content of the invention
Present invention aim at providing one kind { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino]
Ethyl }-t-butyl carbamate preparation method, to overcome existing technological deficiency.
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl } the tertiary fourth of-carbamic acid
The preparation method of ester, it is characterised in that comprise the following steps：
Formula (1) compound is suspended in solvent, formula (2) compound and alkali is added, is reacted 6～12 hours,
Formula (3) compound is filtrated to get, reaction equation is as follows：
Wherein
R is Cl, Br, I or tolysulfonyl epoxide；
Alkali used be DBU (carbon -7- alkene of 1,8- diazabicylo 11), LDA (lithium diisopropylamine),
NaHMDS (sodium hexamethyldisilazide), KHMDS (potassium hexamethyldisilazide) and its mixing
Thing；It is preferred that DBU and NaHMDS；
Formula (1) compound is 1 with the mol ratio of formula (2) compound：1～8；
Alkali is 1～10 with the mol ratio of formula (2) compound:1；
Reaction temperature is 10～100 DEG C, preferably 20～30 DEG C；
Solvent for use is acetonitrile, THF, DMSO, DMF, NMP and its mixture, preferred acetonitrile, THF
And DMSO.
The present invention's focuses on, and using toxicity less formula (2) compound toxic articles ethylene methacrylic ketone is substituted,
And it is surprised to find that to use the catalytic reactions such as DBU, LDA, NaHMDS, KHMDS, can be with 90%
More than obtain formula (3) compound in high yield, the HPLC contents of crude product reach more than 99.5%, and use
The conventional K of nucleophilic substitution2CO3/ KI/ systems and triethylamine/KI systems can not react fully and carry out.
The purity and yield for obtaining formula (3) compound using different base catalyzed reactions is as shown in the table：
The test result of the differential responses condition of table 1
In sum, the preparation method that the present invention is provided has the advantage that：
(1) avoid using toxic articles ethylene methacrylic ketone, reagent toxicity used is less；
(2) mild condition, post-processing operation is simple, is adapted to industrialized production；
(3) byproduct of reaction is few, and gained formula (3) compound purity and yield are higher, Ke Yi Wei Su Woleisheng
Synthesis provide high-quality medicine intermediate.
Specific embodiment
The present invention is further described in detail with reference to specific embodiment, the embodiment for being given is only
In order to illustrate the present invention, rather than in order to limit the scope of the present invention.
The preparation of starting material compound (1)
A：The preparation of 2- sulfydryl -5- chlorobenzene diozaioles
By 2- amino -4- chlorophenols (100g, 0.69mol), ehtyl potassium xanthate (13.3g, 0.83mol)
Add in tetra- mouthfuls of reaction bulbs of 3L with absolute ethyl alcohol 1500ml, be heated to back flow reaction 8 hours.Decompression is steamed
Absolute ethyl alcohol, residue adds 1300ml water dissolves, filters white solid after being acidified with 100ml concentrated hydrochloric acids
Body 122.6g, yield 94.9%.1H NMR(400MHz,d6-DMSO):(s, 1H, heavy water is exchanged and disappeared δ 13.998
Lose), 7.513 (d, 1H, J=8.8Hz), 7.302-7.277 (m, 2H).
B：{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (compound of formula 1)
Prepare
2- sulfydryls -5- chlorobenzene diozaioles (100g, 0.54mol) and dichloromethane 1200ml are added to 3L tetra-
In mouth reaction bulb, stirring adds oxalyl chloride (102.6g, 0.81mol), and DMF 395ml are added dropwise, and normal temperature is anti-
Answer 30 minutes, triethylamine (192g, 1.89mol) and 1- (t-butyl carbamate) ethylenediamine (103.7 is added dropwise
G, 0.65mol), normal-temperature reaction 1 hour.Water 1200ml is added, organic layer is separated, evaporated under reduced pressure must be consolidated
Liquid mixture, with acetonitrile/water yellow solid 110g, yield 65.5% are refining to obtain.1HNMR(400MHz,CDCl3):δ 7.285 (d, 1H, J=2Hz), 7.103 (d, 1H, J=8.4Hz), 6.965 (dd, 1H, J=
8.4,2Hz), 4.967 (s, 1H), 3.566 (t, 2H, J=5.6Hz), 3.416 (t, 2H, J=5.6Hz), 1.407 (s, 9H).
Embodiment 1
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (6.8g, 0.064mol) of 4-, DBU (19.5g, 0.128mol) and acetonitrile 60ml are added to 250ml
In four mouthfuls of reaction bulbs, 20～30 DEG C are reacted 9 hours.Add water 120ml, stirs 1 hour, filters, and obtains white
Solid 12g, yield 98%.1HNMR(400MHz,CDCl3):δ 7.272 (d, 1H, J=2Hz), 7.114 (d, 1H, J=8.4Hz), 6.947 (dd, 1H, J=
8.4,2Hz), 4.864 (s, 1H), 3.754 (t, 2H, J=2.8Hz), 3.653 (t, 2H, J=6.4
), Hz 3.398 (t, 2H, J=5.6Hz), 2.908 (t, 2H, J=6.4Hz), 2.165 (s, 3H), 1.347 (s, 9H).
Embodiment 2
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
4- (tolysulfonyl epoxide) -2- butanone (15.5g, 0.064mol), DBU (19.5g, 0.128mol) and THF
60ml is added in tetra- mouthfuls of reaction bulbs of 250ml, and 20～30 DEG C are reacted 9 hours.Add water 120ml, stirring 1
Hour, filter to obtain white solid 11.7g, yield 95.5%.
Embodiment 3
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (6.8g, 0.064mol) of 4-, LDA (13.8g, 0.128mol) and acetonitrile 60ml are added to 250ml
In four mouthfuls of reaction bulbs, 20～30 DEG C are reacted 9 hours.Add water 120ml, stirs 1 hour, filters white solid
Body 11.4g, yield 93.1%.
Embodiment 4
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (6.8g, 0.064mol) of 4-, NaHMDS (23.6g, 0.128mol) and DMSO 100ml add
Enter in tetra- mouthfuls of reaction bulbs of 250ml, 20～30 DEG C are reacted 9 hours.Add water 120ml, stirs 1 hour,
Filter to obtain white solid 11.6g, yield 94.7%.
Embodiment 5
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (13.6g, 0.128mol) of 4-, DBU (77.8g, 0.512mol) and THF 60ml and it is added to
20～30 DEG C are reacted 9 hours in tetra- mouthfuls of reaction bulbs of 250ml.Add water 50ml, stirs 1 hour, filters in vain
Color solid 11.6g, yield 94.7%.
Embodiment 6
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (5.1g, 0.048mol) of 4-, DBU (9.8g, 0.064mol) and acetonitrile 60ml are added to 250ml
In four mouthfuls of reaction bulbs, back flow reaction (82 DEG C) 6 hours.Add water 120ml, stirs 1 hour, filters in vain
Color solid 11.1g, yield 91%.
Embodiment 7
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (5.1g, 0.048mol) of 4-, DBU (9.8g, 0.064mol) and DMF 50ml and it is added to
In tetra- mouthfuls of reaction bulbs of 250ml, 20～30 DEG C are reacted 9 hours.Add water 120ml, stirs 1 hour, filters
Obtain white solid 11.4g, yield 93.1%.
Embodiment 8
{ 2- [(base of 5- chlorobenzenes benzoxazoles -2)-(3- ketone-butyl)-amino] ethyl }-t-butyl carbamate (chemical combination
Thing 3) preparation
By { 2- [(base of 5- chlorobenzenes benzoxazoles -2)-amino] ethyl }-t-butyl carbamate (10g, 0.032mol),
The chloro- 2- butanone (5.1g, 0.048mol) of 4-, KHMDS (12.8g, 0.064mol) and NMP 50ml and addition
To in tetra- mouthfuls of reaction bulbs of 250ml, 20～30 DEG C are reacted 9 hours.Add water 120ml, stirs 1 hour, mistake
Filter to obtain white solid 11.3g, yield 92.2%.
Claims (9)
1. a kind of preparation method of Su Woleisheng intermediates formula (3) compound, it is characterised in that including following
Step：
Formula (1) compound is suspended in solvent, formula (2) compound and alkali is added, is reacted 6～12 hours,
Formula (3) compound is filtrated to get, reaction equation is as follows：
Wherein
R is Cl, Br, I or tolysulfonyl epoxide.
2. method according to claim 1, it is characterised in that alkali used is selected from DBU, LDA,
NaHMDS, KHMDS or its mixture.
3. method according to claim 2, it is characterised in that alkali used is DBU or NaHMDS.
4. method according to claim 1, it is characterised in that formula (1) compound is changed with formula (2)
The mol ratio of compound is 1:1～8.
5. method according to claim 1, it is characterised in that the mol ratio of alkali and formula (2) compound
For 1～10:1.
6. method according to claim 1, it is characterised in that reaction temperature is 10～100 DEG C.
7. method according to claim 6, it is characterised in that reaction temperature is 20～30 DEG C.
8. method according to claim 1, it is characterised in that the solvent for using is selected from acetonitrile, THF,
DMSO, DMF, NMP or its mixture.
9. method according to claim 8, it is characterised in that the solvent for using is acetonitrile, THF or
DMSO。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510736723.2A CN106632121A (en) | 2015-11-03 | 2015-11-03 | Method for preparing important Suvorexant intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510736723.2A CN106632121A (en) | 2015-11-03 | 2015-11-03 | Method for preparing important Suvorexant intermediate |
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| Publication Number | Publication Date |
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| CN106632121A true CN106632121A (en) | 2017-05-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510736723.2A Pending CN106632121A (en) | 2015-11-03 | 2015-11-03 | Method for preparing important Suvorexant intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912519A (en) * | 2019-03-29 | 2019-06-21 | 成都美域高制药有限公司 | A kind of synthetic method of Su Woleisheng intermediate |
| CN110272925A (en) * | 2018-03-16 | 2019-09-24 | 中国科学院天津工业生物技术研究所 | A kind of enzymatic-process preparation method of Su Woleisheng key intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012148553A1 (en) * | 2011-03-03 | 2012-11-01 | Merck Sharp & Dohme Corp. | Process for the preparation of an orexin receptor antagonist |
| WO2013169610A1 (en) * | 2012-05-09 | 2013-11-14 | Merck Sharp & Dohme Corp. | Process for the preparation of an intermediate for 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 |
| IN2013MU02168A (en) * | 2013-06-26 | 2015-06-12 | Arch Pharmalabs Ltd |
-
2015
- 2015-11-03 CN CN201510736723.2A patent/CN106632121A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012148553A1 (en) * | 2011-03-03 | 2012-11-01 | Merck Sharp & Dohme Corp. | Process for the preparation of an orexin receptor antagonist |
| WO2013169610A1 (en) * | 2012-05-09 | 2013-11-14 | Merck Sharp & Dohme Corp. | Process for the preparation of an intermediate for an orexin receptor antagonist |
| IN2013MU02168A (en) * | 2013-06-26 | 2015-06-12 | Arch Pharmalabs Ltd | |
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110272925A (en) * | 2018-03-16 | 2019-09-24 | 中国科学院天津工业生物技术研究所 | A kind of enzymatic-process preparation method of Su Woleisheng key intermediate |
| CN109912519A (en) * | 2019-03-29 | 2019-06-21 | 成都美域高制药有限公司 | A kind of synthetic method of Su Woleisheng intermediate |
| CN109912519B (en) * | 2019-03-29 | 2022-07-05 | 成都美域高制药有限公司 | Synthetic method of suvorexant intermediate |
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Application publication date: 20170510 |