CN106632257B - The synthetic method of GSK961081 and its intermediate - Google Patents
The synthetic method of GSK961081 and its intermediate Download PDFInfo
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Abstract
The present invention relates to the new method for preparing drug GSK961081 and its intermediate, this method not only avoids the isocyanates reagent using severe toxicity compared with existing synthetic method, and synthetic route is simple, more convenient operation, yield is higher, is more suitable for industrialized production.
Description
Technical field
The present invention relates to the synthetic methods of GSK961081 and its intermediate, belong to pharmaceutical technology field.
Background technique
Chronic Obstructive Pulmonary Disease (abbreviation COPD) brings serious prestige to the health of the public as the fifth-largest cause of the death in the whole world
The side of body.Bronchodilator is the first-line treatment drug for controlling the critical treatment drug and COPD of COPD symptom.Conventional branch gas
Enlargement of pipe agent mainly contains two kinds of ingredients: β 2 receptor agonist and m receptor antagonist.
GSK961081 be GlaxoSmithKline PLC and Theravance company cooperative research and development Long-effect β_2 reactant excitomotor agent and M by
Body antagonist compound medicine, chemical structural formula are as follows:
The most significant feature of GSK961081 is that β 2 receptor agonist and m receptor antagonist are incorporated into a small molecule,
It is put into the conventional combination medicament in an inhalator compared to by two kinds of drugs of β 2 receptor agonist and m receptor antagonist,
GSK961081 has preferable curative effect to treatment Chronic Obstructive Pulmonary Disease, has fabulous listing prospect.
About the synthetic method of GSK961081, pertinent literature report is considerably less.In general, synthetic route is mostly with following
Two compound formula (X)s and formula (Y) are synthesis material, by Schiff reaction, reduction, are deprotected obtained GSK961081 (example
Such as patent document WO2007090859, disclosed by US20060035931).
It is always the problem of this field about the synthesis of formula (X) compound.The conjunction of formula (X) compound reported at present
At route (referring to Hughes, Adam D. et al., J.Med.Chem.2015,58 (6), 2609-2622), on the one hand, wherein adopt
With severe toxicity and expensive isocyanate ester compound is starting material, and the complexity and risk of step post-processing are not allowed to neglect
Depending on unsuitable industrialized production, on the other hand, the reaction yield of the final step of the synthetic route is lower, causes entirely to close
It is lower at the reaction yield of route.
Therefore, it is extremely urgent to develop a kind of new method for preparing GSK961081.
Summary of the invention
In view of the above problem and/or other problems of the relevant technologies, one aspect of the present invention provides a kind of as following formula (G) changes
The synthetic method of object is closed,
The synthetic method at least includes the following steps:
Step 1): nucleophilic occurs in the presence of an inorganic base and takes using following formula (1-a) compound and formula (1-b) compound
Generation reaction generates following formula (1) compound;
Wherein, the R group in formula (1-b) compound and formula (1) compound is amino protecting groups;
Step 2): formula (1) compound generates following formula (2) compound by de- R base reaction;
Step 3): formula (2) compound and following formula (3) compound occur addition reaction and generate following formula (4) compound;
The formula (G) compound finally is made via the formula (4) compound.
Another aspect of the present invention provides a kind of synthetic method of pharmaceutical intermediate, and the pharmaceutical intermediate is following formula
(1) compound is the pharmaceutical intermediate of following formula (G) compound;
The synthetic method of formula (1) compound the following steps are included:
Nucleophilic substitution is occurred using following formula (1-a) compound and formula (1-b) compound in the presence of an inorganic base
Generate the formula (1) compound;
Wherein, the R group in formula (1-b) compound and formula (1) compound is the blocking group of amido.
Further aspect of the present invention provides a kind of synthetic method of pharmaceutical intermediate, and the pharmaceutical intermediate is following formula
(4) compound is the pharmaceutical intermediate of following formula (G) compound;
The synthetic method of formula (4) compound the following steps are included:
Addition reaction is occurred using following formula (2) compound and following formula (3) compound and generates formula (4) compound;
The present invention provides the new method for preparing drug GSK961081 and its intermediate, this method and existing synthesis side
Method is compared, and not only avoids the isocyanates reagent using severe toxicity, and synthetic route is simple, more convenient operation, yield is more
Height is more suitable for industrialized production.
Specific embodiment
The present invention is further illustrated by the following examples, but the present invention is not limited to these specific embodiment parties
Formula.
For synthetic drug GSK961081 (formula (G) compound i.e. as described herein), one embodiment of the invention
It is middle to use following steps:
Step 1):
Nucleophilic substitution is occurred using following formula (1-a) compound and formula (1-b) compound in the presence of an inorganic base
Generate following formula (1) compound;
Wherein, the R group in formula (1-b) compound and formula (1) compound is the blocking group of amido.
In a preferred embodiment of the invention, the R group in formula (1-b) compound and formula (1) compound is
Boc, Bn, methyl, acetyl group or substituted or unsubstituted benzoyl;Wherein, refer to phenyl ring about " substituted benzoyl "
At least one upper hydrogen atom replaces;Preferably, substituted benzoyl can be the saturated or unsaturated alkyl of 1~4 carbon
Or the benzoyl that the groups such as alkoxy, nitro, halogen, aromatic hydrocarbons replace.
In the present embodiment, R group Boc.
In a preferred embodiment of the invention, the inorganic base used in the step 1) can for NaH, LDA,
NaHMDS、NaOH、KOH、KHMDS、LiHMDS、CH3ONa or CH3CH2ONa.It is furthermore preferred that in the present embodiment, inorganic base can
Think NaHMDS.
In a preferred embodiment of the invention, reaction dissolvent used by the nucleophilic substitution of the step 1)
It can be tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, ether, 2- methyltetrahydrofuran or N,N-dimethylformamide.
It is furthermore preferred that in the present embodiment, reaction dissolvent is tetrahydrofuran.
In a preferred embodiment of the invention, the nucleophilic substitution of the step 1), in the guarantor of inert gas
Shield is lower to be carried out, and reaction temperature is -50 DEG C~5 DEG C, reaction time 1h-10h.
Wherein, inert gas is helium, neon, argon gas, Krypton and xenon etc..It is furthermore preferred that in the present embodiment, inertia
Gas selects argon gas.
The reaction temperature of nucleophilic substitution about step 1), it is furthermore preferred that -40 DEG C, -30 DEG C, -20 DEG C, -10 DEG C, -
5 DEG C or 0 DEG C.In the present embodiment, reaction temperature is about 0 DEG C.
In a preferred embodiment of the invention, after the nucleophilic substitution of the step 1) is complete, to reaction
Ammonium chloride solution quenching reaction is added in product, and adjusts pH to 5~6, obtains formula (1) compound using extraction.More
Preferably, in the present embodiment, using saturated ammonium chloride solution quenching reaction.
In one embodiment of the invention, the molar ratio of formula (1-a) compound and formula (1-b) compound is 1:
1~1:2.Although for the nucleophilic substitution of step 1), the chemical reaction of formula (1-a) compound and formula (1-b) compound
Molar ratio is 1:1, but is fully reacting, and formula (1-b) compound should be excessive, for example, formula (1-a) compound and formula (1-b) are changed
The molar ratio for closing object is 1:1.2,1:1.3,1:1.5 or 1:1.8.
In the present embodiment, the specific operation process of step 1) is as follows: 38g formula (1-a) compound is dissolved in 100ml tetrahydro
Stirred at 0 DEG C in furans, after be slowly added dropwise 225ml (2M) NaHMDS tetrahydrofuran solution, then by 80g formula (1-b) compound
(R group Boc) is added portionwise into mixed liquor, wait be added dropwise, the reaction was continued 3h, after complete reaction plus saturated ammonium chloride
Solution quenching reaction is adjusted to PH to 5-6, then is extracted with ethyl acetate to get faint yellow solid, and crude yield is up to 70%;
The faint yellow solid of acquisition is accredited as formula (1) compound through hydrogen nuclear magnetic resonance spectrum, and appraising datum is as follows:
1H NMR(dmso-d6,400MHz):δ8.68(s,1H),7.45-7.29(m,9H),4.67-4.61(m,1H),
3.55-3.52(m,2H),3.13-3.01(m,2H),1.71-1.69(m,2H),1.40(s,9H),1.36-1.34(m,2H);
LCMS m/z:found,397.3[M+H]+。
In one embodiment of the invention, formula (1) compound is synthesis formula (G) compound (drug
GSK961081 an important intermediate).
Step 2):
Formula (1) compound obtained through step 1) generates following formula (2) compound by de- R base reaction;
In a preferred embodiment of the invention, in the step 2), presence of formula (2) compound in trifluoroacetic acid
Under carry out de- R reaction;After fully reacting, pH value of solution is adjusted to 8~9, obtains formula (2) compound using extraction.
In the present embodiment, the specific operation process of step 2) is as follows:
62.5g step 1) formula obtained (1) compound is dissolved in 100ml methylene chloride (reaction dissolvent) under ice bath
Stirring, is slow added into 36g trifluoroacetic acid, it is to be added finish to be transferred to react 3h at room temperature, after complete reaction, adjusted after precipitation
Solution PH is saved to 8-9, extraction is drying to obtain white-yellowish solid, and crude yield is up to 98%;
The white-yellowish solid of acquisition is accredited as formula (2) compound through hydrogen nuclear magnetic resonance spectrum, and appraising datum is as follows:
1H NMR(400MHz,CD3OD) δ 7.56 (d, J=7.6Hz, 1H), 7.47-7.21 (m, 8H), 4.66 (m, 1H),
3.00-2.90(m,2H),2.63(m,2H),1.87-1.77(m,2H),1.49(m,2H);LCMS m/z:found,297.3[M+
H]+。
Step 3):
Formula (2) compound and following formula (3) compound that step 2) obtains occur addition reaction and generate following formula (4) chemical combination
Object;
In a preferred embodiment of the invention, the reaction dissolvent of the addition reaction of step 3) is tetrahydrofuran and first
The mixed solution of alcohol, and wherein the volume ratio of tetrahydrofuran and methanol is 9:1~9:9;Preferably, the body of tetrahydrofuran and methanol
Product ratio can be 9:2,9:3,9:4,9:5,9:6,9:7 or 9:8.It is furthermore preferred that in the present embodiment, tetrahydrofuran and methanol
Volume ratio is 9:5.
In a preferred embodiment of the invention, the addition reaction of step 3), reaction temperature are 30 DEG C~90 DEG C, instead
It is 10h~20h between seasonable.About the temperature of addition reaction, it is furthermore preferred that can be 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C or 80 DEG C.
In the present embodiment, the reaction temperature of the addition reaction of step 3) is 60 DEG C.
In a preferred embodiment of the invention, in step 3), after addition fully reacting, precipitation, then use second
Acetoacetic ester crosses column and obtains formula (4) compound.
In the present embodiment, the specific operation process of step 3) is as follows:
Resulting 46g formula (2) compound of step 2) and 38g formula (3) compound are dissolved in 100ml tetrahydrofuran and methanol
In the mixed solvent (wherein, the volume ratio of tetrahydrofuran and methanol is 9:5), 16h is reacted at 60 DEG C, after complete reaction, is taken off
It is molten, then column is crossed with ethyl acetate up to white solid, reaction yield 71%;
The white solid of acquisition is accredited as formula (4) compound through hydrogen nuclear magnetic resonance spectrum, and appraising datum is as follows:
1H NMR(dmso-d6,400MHz):δ10.18(s,1H),8.69(s,1H),8.25(s,1H),7.72(s,1H),
7.42-7.32 (m, 9H), 5.13 (s, 2H), 4.58-4.52 (m, 1H), 3.41 (s, 1H), 3.89 (s, 3H), 2.76 (s, 2H),
2.65 (s, 4H), 2.55 (t, J=8.8Hz, 2H), 1.81 (d, J=9.2Hz, 2H), 1.55 (d, J=9.2Hz, 2H);LCMS
m/z:found,538.3[M+H]+。
In one embodiment of the invention, formula (4) compound is also synthesis formula (G) compound (drug
GSK961081 an important intermediate).
In one embodiment of the invention, the process from formula (4) compound synthesis formula (G) compound include with
Lower step:
Step 4): step 3) resulting formula (4) compound is generated into following formula (5) compound by Swern oxidation reaction;
In a preferred embodiment of the invention, the Swern oxidation reaction in step 4) is with sulfur trioxide pyridine
Activator, dimethyl sulfoxide are oxidant, and DIPEA is alkali.It is furthermore preferred that the reaction temperature of Swern oxidation reaction is -30 DEG C~0
DEG C, reaction time 2h-8h.It is furthermore preferred that adding water quenching reaction after complete reaction, reuses methylene chloride and extract, precipitation,
Up to formula (5) compound.
In the present embodiment, the molar ratio between formula (4) compound, dimethyl sulfoxide, DIPEA and sulfur trioxide pyridine is 1:
10:5:5.
In the present embodiment, the specific operation process of step 4) is as follows:
By resulting 59g formula (4) compound of step 3), 300ml dichloromethane is dissolved in 70g DIPEA and 86g dimethyl sulfoxide
In alkane, 10min is stirred at -20 DEG C, after be added portionwise 88g sulfur trioxide pyridine, the 6h to be added that finishes that the reaction was continued, wait react
200ml water quenching reaction is added after completely, rear methylene chloride extraction, dry, precipitation reaches up to faint yellow solid, crude yield
98%;
The faint yellow solid of acquisition is accredited as formula (5) compound through hydrogen nuclear magnetic resonance spectrum, and appraising datum is as follows:
1H NMR(dmso-d6,400MHz):δ10.71(s,1H),10.18(s,1H),8.68(s,1H),8.25(s,
1H),7.71(s,1H),7.42-7.31(m,9H),4.57-4.52(m,1H),3.88(s,3H),2.78(s,2H),2.63(s,
4H), 2.52 (t, J=8.8Hz, 2H), 1.80 (d, J=9.2Hz, 2H), 1.54 (d, J=9.2Hz, 2H);LCMS m/z:
found,536.2[M+H]+。
Step 5): with following formula (6) compound Schiff is occurred into for the resulting formula of step 4) (5) compound and reacts it
Afterwards, using reduction reaction, following formula (7) compound is generated;
In a preferred embodiment of the invention, the Schiff reaction in step 5), reaction dissolvent use dichloro
The mixed solution of methane and methanol, and wherein the volume ratio of methylene chloride and methanol is 1:1~1:5.Preferably, Schiff is anti-
The reaction temperature answered is 25 DEG C~50 DEG C, and the reaction time is 2h~5h.
In another preferred embodiment of the present invention, the reduction reaction in step 5), using triacetoxy borohydride hydrogen
Change sodium as reducing agent.It is furthermore preferred that the reaction temperature of reduction reaction is 0 DEG C~25 DEG C, the reaction time is 10h~for 24 hours.
In a preferred embodiment of the invention, in step 5), formula (5) compound, formula (6) compound and triacetyl
The molar ratio of oxygroup sodium borohydride is 1:(1.0~1.5): (1~3).
In the present embodiment, the specific operation process of step 5) is as follows:
58.8g formula (5) compound and 45g formula (6) compound that step 4) obtains are dissolved in 200ml methylene chloride and methanol
In the mixed solvent (wherein, the volume ratio of methylene chloride and methanol be 1:1), react 2h at 25 DEG C, after be added portionwise it is total
The reaction was continued at 70g sodium triacetoxy borohydride, with 25 DEG C for 24 hours, and after complete reaction plus water quenching is gone out, rear methylene chloride extraction
It takes, dry, precipitation is up to white-yellowish solid (i.e. formula (7) compound), crude yield 85%.
Step 6): step 5) resulting formula (7) compound is by deprotection acquisition formula (G) compound.
In a preferred embodiment of the invention, formula (7) compound is obtained by the deprotection of triethylamine hydrofluoride
Formula (G) compound.It is furthermore preferred that the molar ratio of formula (7) compound and triethylamine hydrofluoride is 1:1~1:5.It is furthermore preferred that
Reaction temperature is 25 DEG C -40 DEG C, and the reaction time is for 24 hours~72h.
In the present embodiment, the specific operation process of step 6) is as follows:
20g formula (7) compound that step 5) obtains is dissolved in 100ml methylene chloride, 12ml triethylamine hydrofluoric acid is added
Salt reacts 48h at 25 DEG C, rear that 5.6g 1 is added, and 2- ethionic acid hydrate stirs 2h, after the precipitation of a large amount of solids filtering be
15g crude product formula (G) compound (drug GSK961081) is obtained, further washs to obtain sterling with methanol.
The product of acquisition is accredited as formula (G) compound through hydrogen nuclear magnetic resonance spectrum, and appraising datum is as follows:
1H NMR(300MHz,CD3OD): δ 8.07 (d, J=9.8Hz, 1H), 7.76 (s, 1H), 7.60-7.15 (m, 11H),
7.0 (d, J=8.5Hz, 1H), 6.56 (d, J=10.7Hz, 1H), 5.36 (dd, J1=8.5, J2=3.5Hz, 1H), 4.79 (m,
1H),4.38-4.05(m,2H),3.80(s,3H),3.56(m,4H),3.22-2.89(m,6H),2.35-1.59(m,4H)
.LCMS m/z:found,740.1[M+H]+。
It should be appreciated that although this specification is described in terms of embodiments, but not each embodiment only includes one
A independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should will say
As a whole, the technical solution in each embodiment may also be suitably combined to form those skilled in the art can for bright book
With the other embodiments of understanding.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
Claims (18)
1. a kind of synthetic method of such as following formula (G) compound,
The synthetic method at least includes the following steps:
Step 1): it is anti-that nucleophilic displacement of fluorine is occurred using following formula (1-a) compound and formula (1-b) compound in the presence of an inorganic base
Following formula (1) compound should be generated;
Wherein, the R group in formula (1-b) compound and formula (1) compound is Boc, Bn, methyl, acetyl group or substitution or does not take
The benzoyl in generation;
Step 2): formula (1) compound generates following formula (2) compound by de- R base reaction;
Step 3): formula (2) compound and following formula (3) compound occur addition reaction and generate following formula (4) compound;
The formula (G) compound finally is made via the formula (4) compound.
2. synthetic method as described in claim 1, it is characterised in that:
The inorganic base used in the step 1) is NaH, LDA, NaHMDS, NaOH, KOH, KHMDS, LiHMDS, CH3ONa or
CH3CH2ONa。
3. synthetic method as claimed in claim 2, it is characterised in that:
Reaction dissolvent used by the nucleophilic substitution of the step 1) is tetrahydrofuran, 1,4- dioxane, dimethyl Asia
Sulfone, ether, 2- methyltetrahydrofuran or N,N-dimethylformamide.
4. synthetic method as claimed in claim 3, it is characterised in that:
The nucleophilic substitution of the step 1) carries out under the protection of inert gas, and reaction temperature is -50 DEG C~5 DEG C, reaction
Time is 1h-10h.
5. synthetic method as claimed in claim 3, it is characterised in that:
After nucleophilic substitution to the step 1) is complete, ammonium chloride solution quenching reaction is added into reaction product, and
PH to 5~6 is adjusted, obtains formula (1) compound using extraction.
6. synthetic method as described in claim 1, it is characterised in that:
In the step 1), the molar ratio of formula (1-a) compound and formula (1-b) compound is 1:1~1:2.
7. synthetic method as described in claim 1, it is characterised in that:
In the step 2), formula (2) compound carries out de- R reaction in the presence of trifluoroacetic acid;After fully reacting,
PH value of solution is adjusted to 8~9, obtains formula (2) compound using extraction.
8. synthetic method as described in claim 1, it is characterised in that:
In the step 3), the molar ratio of formula (2) compound and formula (3) compound is 1:1~1:2.
9. synthetic method as described in claim 1, it is characterised in that:
The reaction dissolvent of the addition reaction of the step 3) be tetrahydrofuran and methanol mixed solution, and wherein tetrahydrofuran with
The volume ratio of methanol is 9:1~9:9.
10. synthetic method as claimed in claim 9, it is characterised in that:
The addition reaction of the step 3), reaction temperature are 30 DEG C~90 DEG C, and the reaction time is 10h~20h.
11. synthetic method as claimed in claim 10, it is characterised in that:
In the step 3), after addition fully reacting, precipitation, then cross column with ethyl acetate and obtain formula (4) compound.
12. the synthetic method as described in any one of claim 1 to 11, it is characterised in that:
It is described via the formula (4) compound be made the formula (G) compound process the following steps are included:
Step 4): formula (4) compound generates following formula (5) compound by Swern oxidation reaction;
13. synthetic method as claimed in claim 12, it is characterised in that:
Swern oxidation reaction in the step 4), using sulfur trioxide pyridine as activator, dimethyl sulfoxide is oxidant, DIPEA
For alkali.
14. synthetic method as claimed in claim 12, it is characterised in that:
The process that the formula (G) compound is made via the formula (4) compound still further comprises following steps:
Step 5): formula (5) compound occurs Schiff with following formula (6) compound and reacts and then by reduction reaction, life
At following formula (7) compound;
Step 6): formula (7) compound is by deprotection acquisition formula (G) compound.
15. synthetic method as claimed in claim 14, it is characterised in that:
Schiff reaction in the step 5), reaction dissolvent use the mixed solution of methylene chloride and methanol, and wherein two
The volume ratio of chloromethanes and methanol is 1:1~1:5.
16. synthetic method as claimed in claim 14, it is characterised in that:
Reduction reaction in the step 5), using sodium triacetoxy borohydride as reducing agent.
17. synthetic method as claimed in claim 14, it is characterised in that:
In the step 6), formula (7) compound is deprotected acquisition formula (G) compound by triethylamine hydrofluoride.
18. a kind of synthetic method of pharmaceutical intermediate,
The pharmaceutical intermediate is following formula (1) compound, is the pharmaceutical intermediate of following formula (G) compound;
The synthetic method of formula (1) compound the following steps are included:
Nucleophilic substitution occurs in the presence of an inorganic base using following formula (1-a) compound and formula (1-b) compound to generate
Formula (1) compound;
Wherein, the R group in formula (1-b) compound and formula (1) compound is Boc, Bn, methyl, acetyl group or substitution or does not take
The benzoyl in generation.
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