CN107382785A - One planting sand storehouse must bent key intermediate preparation method - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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Abstract
The present invention relates to pharmaceutical technology field, specifically, is related to a kind of preparation method of new Sha Kubi song key intermediates.Sha Kubi song key intermediates are prepared using method provided by the invention, reaction condition is gentle, green, and yield is higher than existing preparation method, economical and effective, suitable for large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically, be related to a planting sand storehouse must bent key intermediate preparation method.
Background technology
In July, 2015, FDA approval listings Novartis since the dawn of human civilization most soul-stirring cardiotonic agents Sha Kubi it is bent/
Valsartan (Sha Kubi songs/Valsartan), trade name Entresto, by the current cardiovascular drugs most successful on the market of challenge.
Entresto is the ARNI inhibitor class medicines of first success of the test.ARNI inhibitor is a kind of angiotensins
Inhibitor, but it can strengthen the effect of endogenous natriuretic peptide (vasodilator) simultaneously.The medicine is a kind of economic benefits and social benefits vasotonia
Plain acceptor enkephalinase inhibitor, there is unique binding mode, be believed to reduce the strain of failure heart.Entresto
Combine Valsartan (Diovan, the common name of Novartis：Valsartan) and experimental drug AHU-377 (Sha Kubi is bent).AHU377 is (husky
Storehouse must be bent) threat can be blocked to be responsible for the mechanism of action of 2 kinds of polypeptides to reduce blood pressure, Diovan can then improve vasodilation, stimulate
Body drains sodium and water, and both play pharmacological action jointly together by reaction forming.
J.Med.Chem.1995,38,1689-1700. disclose a planting sand storehouse must bent intermediate preparation method, its close
It is as follows into route:
The raw material D- TYRs of this method are alpha-non-natural amino acid, and price is costly；During use trifluoromethanesulfonic acid
Acid anhydride, it is not only expensive, and also activity is very strong, requires very high to production operation.
Patent WO2014032627 disclose a planting sand storehouse must bent intermediate preparation method, synthetic route is as follows：
Although this method route is shorter, the relative low price of supplementary material, poisonous had using a large amount of in ammonifying process
Evil reagent triphenyl phosphorus, environmental pollution are big；RMgBr activity is higher simultaneously, and operation requires high, and big production is difficult.
Patent CN200780002319.6 disclose a planting sand storehouse must bent intermediate preparation method, synthetic route is as follows：
The biology enzyme fractionation technology that this method is used is high to reaction condition requirement, is not suitable for industrialized production, and biology
The expensive of enzyme, cost are higher.
WO2011035569 disclose a planting sand storehouse must bent intermediate preparation method, its synthetic route is as follows:
This method route is longer, is just split using traditional method for splitting, and yield is relatively low, and competitiveness is weak.
In view of the bent good prospect in medicine of Sha Kubi, it is therefore desirable to develop a kind of economic, safety Sha Kubi song intermediates
Preparation method.
The content of the invention
It is an object of the invention to provide a kind of preparation method of economic, safety Sha Kubi song key intermediates.
Technical scheme is used by the present invention solves above-mentioned technical problem：One planting sand storehouse must bent key intermediate preparation
Method, comprise the following steps：
(1) compound of formula I obtains Formula II compound through reduction；
Wherein, R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；The C1~6Alkyl includes but is not limited to first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and the tert-butyl group；The sulfonate group include trifluoromethanesulfonic acid ester group and
P-methyl benzenesulfonic acid ester group etc.；
(2) amino of Formula II compound is protected to obtain formula III compound in the basic conditions through Boc；
(3) formula III compound obtains formula IV compound through coupling；
Preferably, the R1For chlorine, bromine, iodine, p-toluenesulfonyl or trifluoromethanesulfonic acid ester group.
Preferably, the R2For C1~4Alkyl, benzyl or H.
Preferably, the reducing agent that reduction uses in the step (1) includes lithium aluminium hydride reduction, boron hydride and its derivative；
Boron hydride/metal salt system；Boron hydride/ether sulfuric system；Wherein, the boron hydride includes：Lithium borohydride, boron hydrogen
Change sodium and potassium borohydride；Metal salt system includes：Alkaline-earth halide, lanthanide series metal halide and halogenated transition metal
Thing；The hydroboric derivatives include sodium cyanoborohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride etc..
Preferably, the solvent that reduction uses in the step (1) is tetrahydrofuran or methanol.
Preferably, solvent used in the step (2) includes tetrahydrofuran/water, acetonitrile/water, dichloromethane or dioxy
Six rings.
Preferably, alkali used in the step (2) includes sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine.
Preferably, the coupling mode of the step (3) includes Suzuki couplings, Negishi is coupled, Kumada is coupled,
Stille is coupled or Hiyama couplings.
Preferably, the catalyst used in the step (3) includes：Palladium catalyst and Raney nickel；Part includes：Phosphorus is matched somebody with somebody
Body, nitrogen ligand or carbon part.
Preferably, the phenyl substrate used in the step (3) includes：Phenyl boric acid and its derivative, phenyl zincon, benzene
Base azoviolet, phenyl tin reagent or phenyl silica reagent.
Preferably, the solvent used in the step (3) includes ether, tetrahydrofuran, dioxane or toluene.
Present invention also offers the second planting sand storehouse must bent key intermediate preparation method, comprise the following steps：
(1) compound of formula I is protected to obtain Formula II a compounds through Boc；
Wherein, R1For R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；The C1~6Alkyl includes but unlimited
In methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and the tert-butyl group；The sulfonate group includes triflate
Base and p-methyl benzenesulfonic acid ester group etc.；
(2) amino of Formula II a compounds obtains the compound of formula III through reduction；
(3) formula III compound obtains the compound of formula IV through coupling
Preferably, solvent used in the step (1) includes tetrahydrofuran/water, acetonitrile/water, dichloromethane or dioxy
Six rings.
Preferably, alkali used in the step (1) includes sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine.
Preferably, the reducing agent that reduction uses in the step (2) includes lithium aluminium hydride reduction, boron hydride and its derivative；
Boron hydride/metal salt system；Boron hydride/ether sulfuric system；Wherein, the boron hydride includes：Lithium borohydride, boron hydrogen
Change sodium and potassium borohydride；Metal salt system includes：Alkaline-earth halide, lanthanide series metal halide and halogenated transition metal
Thing；The hydroboric derivatives include sodium cyanoborohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride.
Preferably, the solvent that reduction uses in the step (2) is tetrahydrofuran or methanol.
Preferably, the coupling mode of the step (3) includes Suzuki couplings, Negishi is coupled, Kumada is coupled,
Stille is coupled or Hiyama couplings.
Preferably, the catalyst used in the step (3) includes：Palladium catalyst and Raney nickel；Part includes：Phosphorus is matched somebody with somebody
Body, nitrogen ligand or carbon part.
Preferably, the phenyl substrate used in the step (3) includes：Phenyl boric acid and its derivative, phenyl zincon, benzene
Base azoviolet, phenyl tin reagent or phenyl silica reagent.
Preferably, the solvent used in the step (3) includes ether, tetrahydrofuran, dioxane or toluene.
The invention has the advantages that the preparation method of Sha Kubi songs key intermediate provided by the invention, thirdly step is anti-
Mild condition, green is answered, and yield is higher than existing preparation method, economical and effective, suitable for large-scale industrial production.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of compound ii；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of compound III；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of compounds Ⅳ；
Fig. 4 is compound IIa hydrogen nuclear magnetic resonance spectrogram.
Embodiment
Illustrate technical scheme, but protection scope of the present invention not limited to this below by way of specific embodiment.
Embodiment 1：Compound of formula I obtains the compound (R of formula II through reduction1For I, R2For H)
9.75g sodium borohydrides are added in 1L there-necked flasks, added in 300mL tetrahydrofurans, ice salt bath is cooled to 0 DEG C, adds
Enter 30g compound I, stirring is broken up；It is another to take 50mL single port bottles, 10mL ether is added, the 7.2mL concentrated sulfuric acids are added dropwise under ice salt bath；0℃
Under, the ether sulfuric solution that will configure is slowly dropped in above-mentioned 1L there-necked flasks, and drop finishes, and 24h is stirred at room temperature.To reaction solution
Middle addition 10mL methanol, control temperature are no more than 10 DEG C, then add the 300mL 5N NaOH aqueous solution, then organic solvent is steamed
Remove, residue backflow 3h, be cooled to room temperature, 100mL dichloromethane extracts three times, merges organic layer, organic layer saturation chlorination
Sodium washs, and anhydrous sodium sulfate drying, is spin-dried for obtaining white solid, i.e. compound (II) 22.3g, yield 78%.Compound ii
Nmr analysis data are as follows：1H NMR (500MHz, DMSO-d6) δ 7.62 (d, J=7.9Hz, 1H), 7.03 (d, J=7.9Hz,
1H), 3.26 (dd, J=10.4,5.0Hz, 1H), 3.17 (dd, J=10.4,6.3Hz, 1H), 2.82 (p, J=5.8Hz, 1H),
2.64 (dd, J=13.3,5.4Hz, 1H), 2.36 (dd, J=13.3,7.9Hz, 1H), 1.33 (s, 1H) collection of illustrative plates are as shown in Figure 1.
Embodiment 2：The amino of the compound of formula II is protected to obtain the compound (R of formula III through Boc1For I)
10g compound iis are dissolved in 100mL tetrahydrofurans, 50mL water is added and 3.8g sodium carbonate, stirring is broken up.Cooling
To 0~5 DEG C, 8.7g Boc acid anhydrides is added dropwise, drop finishes, warms naturally to room temperature, be stirred overnight.Add 100mL water, 100mL acetic acid
Ethyl ester is extracted three times, merges organic layer, and organic layer is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, is spin-dried for solvent, is added
50mL n-hexanes are beaten, and crystallization is stayed overnight at 0~5 DEG C, are filtered, 40 DEG C of forced air drying 3h, are obtained white solid, i.e. compound III
12.2g, yield 90%.The nmr analysis data of compound III are as follows：1H NMR (500MHz, DMSO-d6) δ 7.61 (d, J=
7.9Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 6.70-6.36 (m, 1H), 4.69 (s, 1H), 3.72-3.46 (m, 1H),
3.45-3.15 (m, 1H), 2.85-2.68 (m, 1H), 2.58-2.34 (m, 1H), 1.50-0.98 (m, 9H) collection of illustrative plates such as Fig. 2 institutes
Show.
Embodiment 3:The compound of formula III obtains the compound (R of formula IV through coupling1For I)
By 4.2g phenyl boric acids, 10g compound IIIs, 0.2g [1,1'- double (diphenylphosphino) ferrocene] palladium chloride adds
In 100mL tetrahydrofurans, stirring is broken up, and adds the sodium carbonate liquor (8.4g sodium carbonate is dissolved in 50mL water) configured, heating
To backflow, four hours are reacted.Organic solvent is spin-dried for, adds 50mL water, is extracted 3 times with 100mL ethyl acetate, is merged organic
Layer, organic layer are washed with saturated sodium-chloride, anhydrous sodium sulfate drying, are added 0.5g activated carbons, room temperature decolouring 1h, are filtered, 100mL
Ethyl acetate filter wash cake, is spin-dried for, and white solid, i.e. compound (IV) 8.2g, yield 83% are recrystallized to obtain with toluene/n-hexane.
The nmr analysis data of compound (IV) are as follows：7.63 (d, J=7.5Hz, 2H), 7.56 (d, J=8Hz, 2H), 7.45 (t, J=
7.5Hz, 2H), 7.34 (t, J=7.5Hz, 1H), 7.29 (d, J=8Hz, 2H), 6.60 (d, J=8.5Hz, 1H), 4.70 (t, J
=5Hz, 1H), 3.62 (m, 1H), 3.36-3.40 (m, 1H), 3.28-3.32 (m, 2H), 2.85-2.88 (m, 1H), 2.59-
2.63 (m, 1H), 1.25 (m, 9H) collection of illustrative plates are as shown in Figure 3.
Embodiment 4：Compound of formula I Boc protects to obtain a compounds (R of formula II1For I, R2For methyl)
50g compounds I is dissolved in 500mL tetrahydrofurans, adds 250mL water and 38.8g sodium carbonate, is cooled to 0 DEG C, drop
Add Boc acid anhydrides, finish and warm naturally to room temperature, reaction is stirred overnight.Reaction finishes, and steams tetrahydrofuran, with 750mL acetic acid second
Ester extracts, and merges organic layer, organic layer is washed with saturated nacl aqueous solution, then is removed water with anhydrous sodium sulfate drying, steams acetic acid
Ethyl ester, the mashing of 150mL n-hexanes is added, crystallization is stayed overnight at 0 DEG C to 5 DEG C, obtains 49g white solids, i.e. compound ii a, yield
83%.'H NMR(CDCl3)δ7.61(d,2H),6.86(d,2H),4.98-4.96(m,lH),4.59-4.55(m,lH),3.72
(s, 3H), 3.08 (q, lH), 2.98 (q, lH), 1.41 (s, 9H) collection of illustrative plates are as shown in Figure 4.
Embodiment 5：The a compound reduction reactions of formula II obtain the compound (R of formula III1For I)
20g compound iis a is dissolved in 400mL tetrahydrofurans, lower addition 14g zinc chloride is stirred, then adds 8g boron hydrogen
Change sodium, have bubble generation, temperature slightly rises.Backflow is warming up to, reacts 4h.Add 600mL water, the extraction of 200ml ethyl acetate
Three times, organic layer is merged, organic layer is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, is spin-dried for organic solvent, adds 40mL second
Acetoacetic ester and the mashing of 80mL n-hexanes, are filtered, forced air drying obtains 15.6g white solids, i.e. compound III, yield 79%.Chemical combination
The nmr analysis data consistent with Example 2 of thing III, collection of illustrative plates is as shown in Figure 2.
It is complete by above-mentioned description, relevant staff using the above-mentioned desirable embodiment according to the present invention as enlightenment
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property scope is not limited to the content on specification, it is necessary to determines its technical scope according to right.
Claims (10)
1. a planting sand storehouse must bent key intermediate preparation method, it is characterised in that comprise the following steps：
(1) compound of formula I obtains Formula II compound through reduction；
Wherein, R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；
(2) amino of Formula II compound is protected to obtain formula III compound in the basic conditions through Boc；
(3) formula III compound obtains formula IV compound through coupling；
2. the preparation method of Sha Kubi songs key intermediate as claimed in claim 1, it is characterised in that the R1For chlorine, bromine,
Iodine or sulfonate group, the sulfonate group include trifluoromethanesulfonic acid ester group and p-methyl benzenesulfonic acid ester group.
3. the preparation method of Sha Kubi songs key intermediate as claimed in claim 1, it is characterised in that the R2For C1~4Alkane
Base, benzyl or H.
4. the preparation method of Sha Kubi songs key intermediate as claimed in claim 1, it is characterised in that in the step (1)
Reducing the reducing agent that uses includes lithium aluminium hydride reduction, boron hydride and its derivative, boron hydride/metal salt system, and boron hydride/
Ether sulfuric system；Wherein, the boron hydride includes：Lithium borohydride, sodium borohydride and potassium borohydride；The metal salt system
Including：Alkaline-earth halide, lanthanide series metal halide and transition metal halide；The hydroboric derivatives include cyano group
Sodium borohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride.
5. the preparation method of Sha Kubi songs key intermediate as claimed in claim 1, it is characterised in that in the step (1)
It is tetrahydrofuran or methanol to reduce the solvent used.
6. the preparation method of Sha Kubi songs key intermediate as claimed in claim 1, it is characterised in that in the step (2)
Solvent used includes tetrahydrofuran/water, acetonitrile/water, dichloromethane or dioxane；Alkali bag used in the step (2)
Include sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine.
7. the preparation method of the Sha Kubi song key intermediates as described in any one of claim 1~6, it is characterised in that described
It is even that the coupling mode of step (3) includes Suzuki couplings, Negishi couplings, Kumada couplings, Stille couplings or Hiyama
Connection.
8. the preparation method of the Sha Kubi song key intermediates as described in any one of claim 1~6, it is characterised in that described
The catalyst used in step (3) includes：Palladium catalyst and Raney nickel；Part includes：Phosphorus part, nitrogen ligand or carbon part；
Phenyl substrate includes：Phenyl boric acid and its derivative, phenyl zincon, phenyl azoviolet, phenyl tin reagent or phenyl silica reagent.
9. the preparation method of the Sha Kubi song key intermediates as described in any one of claim 1~6, it is characterised in that described
The solvent used in step (3) includes ether, tetrahydrofuran, dioxane or toluene.
10. a planting sand storehouse must bent key intermediate preparation method, comprise the following steps：
(1) compound of formula I is protected to obtain Formula II a compounds through Boc；
Wherein, R1For halogen or sulfonate group；R2For C1~6Alkyl, benzyl or H；The C1~6Alkyl include but is not limited to methyl,
Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and the tert-butyl group；The sulfonate group includes trifluoromethanesulfonic acid ester group and to first
Benzene sulfonic acid ester group；
(2) amino of Formula II a compounds obtains the compound of formula III through reduction；
(3) formula III compound obtains the compound of formula IV through coupling
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023029235A1 (en) * | 2021-09-03 | 2023-03-09 | 凯特立斯（深圳）科技有限公司 | Method for preparing sacubitril intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012065958A1 (en) * | 2010-11-16 | 2012-05-24 | Novartis Ag | Method of treating contrast-induced nephropathy |
| CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
| CN105753741A (en) * | 2016-04-26 | 2016-07-13 | 常州制药厂有限公司 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
-
2017
- 2017-08-09 CN CN201710675740.9A patent/CN107382785B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012065958A1 (en) * | 2010-11-16 | 2012-05-24 | Novartis Ag | Method of treating contrast-induced nephropathy |
| CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
| CN105753741A (en) * | 2016-04-26 | 2016-07-13 | 常州制药厂有限公司 | Method for preparing Sacubitril intermediate of anti-heart-failure medicine |
Non-Patent Citations (2)
| Title |
|---|
| GARY M. KSANDER等: "Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors", 《J. MED. CHEM.》 * |
| 吕训磊等: "沙库必曲合成路线图解", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023029235A1 (en) * | 2021-09-03 | 2023-03-09 | 凯特立斯（深圳）科技有限公司 | Method for preparing sacubitril intermediate |
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