CN110041214A - A kind of Melphalan intermediate and preparation method thereof - Google Patents
A kind of Melphalan intermediate and preparation method thereof Download PDFInfo
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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Abstract
The invention discloses a kind of Melphalan intermediates and preparation method thereof, by compound paranitrobenzaldehyde the methanol, salt sour solvent the effects of under acidified obtain, route reaction condition of the present invention is mild, and yield is higher than existing preparation method, economical and effective is suitable for large-scale industrial production.Synthetic route is as follows:
Description
Technical field
The present invention relates to the technical field of compound synthesis, specially a kind of Melphalan intermediate and its preparation side
Method.
Background technique
Melphalan (Melphalan) is antitumor Western medicine, has obvious curative effects to Huppert's disease, is also applied for ovum
Nest cancer；Its general entitled common name: alkeran, Melphalan, L-Sarcolysinum, melophalan.
On October 27th, 2017, the carcinogenic substance inventory edit ginseng that international cancer research institution, the World Health Organization announces
Examine, Melphalan (melphalan) in a kind of carcinogenic substance inventory, melphalan is in 2B class carcinogenic substance inventory.
Past Immunotherapy regimens are often designed as that tumour-specific host immune is mainly stimulated to respond, and can not overcome
Tumour causes the key mechanism of immune evasion (immune evasion), has become the major limitation of the program.It is numerous to be used for
In the definition mechanism of the antineoplastic immune that successively decreases response, it has been assumed that T adjusts cell (Treg), bone marrow derived inhibits cell and tolerance
Property dendritic cells (tolerizing dendritic cells, DCs) are the negative regulator agent that can prevent successful immunization therapy.Certain
One downstream consequence of a little this immune evasion check point approach is the antigen presenting cell activated in immune system input arm
(antigen presenting cells, APCs) number is limited.It needs that immune evasion caused by tumour cell can be overcome crucial
The improvement tumor cell vaccine of mechanism.
Summary of the invention
The purpose of the present invention is to provide a kind of Melphalan intermediates and preparation method thereof, to solve above-mentioned background skill
The problem of being proposed in art.
To achieve the above object, the invention provides the following technical scheme:
A kind of Melphalan intermediate, structural formula such as formula 10:
A kind of Melphalan intermediate the preparation method is as follows:
Step 1:
It is that paranitrobenzaldehyde is added in the mixed liquor of methylene chloride DCM, and 2- acetylaminohydroxyphenylarsonic acid 2- is added by compound 1
(dimethoxyphosphoryl) methyl acetate is reacted to raw material in 0~5 DEG C of dropwise addition DBU and is disappeared；Mistake after 5% aqueous sulfuric acid is added dropwise
Filter, obtains compound 2, synthetic route is as follows after filter cake is dried:
Step 2:
In hydriding reactor, compound 2 described in Step 1 and Rh (ScRp-DuanPhos) (NBD) BF4 are added to methanol
In；Under 0.5~1.0MPa Hydrogen Vapor Pressure, 20 DEG C of reactions to raw material disappear；System is concentrated under reduced pressure to give compound 3, synthesizes road
Line is as follows:
Step 3:
In 6% hydrochloric acid that compound 3 described in Step2 is added to；It disappears in 100 DEG C of reactions to raw material；System is cooled to
It is filtered after room temperature, filter cake is dried to obtain compound 4, synthetic route is as follows:
Step 4:
Compound 4 described in Step3 is added in dehydrated alcohol；In 0~10 DEG C of dropwise addition thionyl chloride；Be warming up to 60 degree it is anti-
It should disappear to raw material；System is cooled to room temperature, and is concentrated under reduced pressure；Ethyl acetate and 10% aqueous sodium carbonate is added, stirs evenly
Organic phase is collected in liquid separation afterwards；After organic phase anhydrous sodium sulfate drying, filtering；Filtrate decompression is concentrated to get compound 5, synthesis
Route is as follows:
Step 5:
Compound 5 and phthalic anhydride described in Step4 are added in toluene, triethylamine is added dropwise；It is warming up to 90 degree extremely
End of reaction；It is cooled to room temperature, 0.5M hydrochloric acid is added, stir liquid separation, collect organic phase；Organic phase is dry using anhydrous sodium sulfate
Dry, mother liquor is collected in filtering, is concentrated under reduced pressure to give compound 6, synthetic route is as follows:
Step 6:
In hydriding reactor, compound 6 described in Step5 and 10% palladium carbon are added in ethyl alcohol；Hydrogenation rises to 2.0MPa
Temperature is to 30 degree to end of reaction；It is cooled to room temperature, filters；Filtrate decompression is concentrated to get compound 7, and synthetic route is as follows:
Step 7:
Compound 7 and ethylene oxide described in Step6 are dissolved into water and acetic acid；It is stirred at room temperature to raw material and is disappeared；Add
Enter ethyl acetate, stirring, collects organic phase at liquid separation；Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give compound 8, closes
It is as follows at route:
Step 8:
Compound 8 described in Step7 is mixed into toluene, 0~10 DEG C of dropwise addition phosphorus oxychloride；70 DEG C are heated to stir to anti-
It should finish；It is concentrated under reduced pressure, adds ethyl acetate and saturated aqueous sodium carbonate, stirring, collects organic phase at liquid separation；Organic phase nothing
Aqueous sodium persulfate is dry, is concentrated under reduced pressure to give compound 9, synthetic route is as follows:
Step 9:
Compound 9 described in Step8 is mixed into 18% hydrochloric acid；100 DEG C of stirrings are heated to end of reaction；It is cooled to
20 degree, filtering, collection mother liquor, mother liquor adjust pH to 6 using sodium acetate aqueous solution, and solid precipitation, filtering obtain after drying filter cake
To compound 10, synthetic route is as follows:
Preferably, filter cake described in Step1 is eluted before drying with water.
Preferably, the successively primary, saturated sodium bicarbonate aqueous solution using water washing before the drying of organic phase described in Step7
Washed once, water washing it is primary.
Compared with prior art, the beneficial effects of the present invention are: reaction has been significantly increased by acidification inducing action
Stereoselectivity, be made higher degree public intermediate, overcome tumour to cause immune evasion (immune evasion)
Key mechanism；Route reaction condition is mild, and yield is higher than existing preparation method, economical and effective, is suitable for large-scale industry
Metaplasia produces.
Specific embodiment
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
The present invention provides a kind of Melphalan intermediate, and the midbody compound synthetic route is as follows:
Embodiment 1:
A kind of Melphalan intermediate the preparation method is as follows:
Step 1:
In the round-bottomed flask of 2L, the paranitrobenzaldehyde of 165.3g is added in the methylene chloride of 2L, is added
2- acetylaminohydroxyphenylarsonic acid 2- (dimethoxyphosphoryl) methyl acetate of 321.2g.In 0 DEG C of dropwise addition 237.4g DBU, after dripping, instead
Monitoring in 2 hours or so to raw material is answered to disappear.5% aqueous sulfuric acid of 900mL, filtering is added dropwise, filter cake is eluted with the water of 450mL.It receives
Collect filter cake.Yellow solid 298.3g, as target product are obtained after filter cake drying.Yield 98.2%, purity 98.1%.
1H NMR (400MHz, CDCl3): δ=8.23 (d, 2H), 7.57 (d, 2H), 7.42 (d, 2H), 3.92 (s, 2H),
2.16(s,3H)。
MS+:265.1
Step 2:
In the hydriding reactor of 2000mL, by substrate, that is, compound 2 of 237.9g and 145mg Rh (ScRp-DuanPhos)
(NBD) BF4 is added in the methanol of 1200mL.Under 0.5MPa Hydrogen Vapor Pressure, 20 degree of reactions, 6 hours or so monitoring to raw materials disappear
It loses.System reduced pressure is dry to obtain yellow solid 239.9g, is target product, that is, compound 3.Yield 99.8%, purity
98.4%, ee 99.5%.
1H NMR (400MHz, CDCl3): δ=8.17 (d, 2H), 7.31 (d, 2H), 6.07 (d, 1H), 4.97 (q, 1H),
3.76(s,1H),3.34(dd,1H),3.22(dd,1H),2.02(s,1H).
MS+:267.1.
[α]=23 (1g/100mL methanol, 20 degree).
R isomers: in the hydriding reactor of 600mL, by the upper step product and 28.2mg Rh (RcSp-DuanPhos) of 44.9g
(NBD) BF4 is added in the methanol of 225mL.Under 0.5MPa Hydrogen Vapor Pressure, 20 degree of reactions, 6 hours or so monitoring to raw materials disappear
It loses.System reduced pressure is dry to obtain yellow solid 45.3g, is target product.Yield 99.8%, purity 98.7%, ee
99.8%.
Step 3:
In the round-bottomed flask of 2L, substrate, that is, compound 3 of 228.0g is added in 6% hydrochloric acid of 900mL.100
Degree reaction monitoring in 20 hours or so to raw material disappears.System is cooled to room temperature, and filter cake is collected in filtering.Filter cake dries to obtain yellow
Solid 202.0g is target product, that is, compound 4.Yield 92.2%, purity 99.2%, ee 99.7%.
1H NMR (400MHz, D2O): δ=8.05 (d, 2H), 7.40 (d, 2H), 4.34 (q, 1H), 3.35 (dd, 1H),
3.26(dd,1H).
MS+:211.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 44.7g is added in 6% hydrochloric acid of 170mL.100
Degree reaction monitoring in 20 hours or so to raw material disappears.System is cooled to room temperature, and filter cake is collected in filtering.Filter cake dries to obtain yellow
Solid 37.6g is target product.Yield 92.0%, purity 99.1%, ee 99.4%.
Step 4:
In the round-bottomed flask of 2000mL, substrate, that is, compound 4 of 184.6g is added in the dehydrated alcohol of 1400mL.
In 0 DEG C of dropwise addition 190.4g thionyl chloride.After being added dropwise, it is warming up to 60 degree of reactions monitoring in 15 hours or so to raw material and disappears.Body
System is cooled to room temperature, and is concentrated under reduced pressure into close dry.1400mL ethyl acetate and 10% aqueous sodium carbonate of 1400mL, stirring is added
Organic phase is collected in liquid separation after 15min.After organic phase anhydrous sodium sulfate drying, filtering.Filtrate decompression is concentrated to get oily liquids
175.2g is target product, that is, compound 5, yield 98.3%, purity 99.0%, ee 99.1%.
1H NMR (400MHz, CDCl3): δ=8.18 (d, 2H), 7.41 (d, 2H), 4.20 (q, 2H), 3.76 (t, 1H),
3.20(dd,1H),3.00(dd,1H),1.27(t,3H).
MS+:239.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 34.5g is added in the dehydrated alcohol of 240mL.0
~10 degree of dropwise addition 33.3g thionyl chlorides.After being added dropwise, it is warming up to 60 degree of reactions monitoring in 15 hours or so to raw material and disappears.Body
System is cooled to room temperature, and is concentrated under reduced pressure into close dry.240mL ethyl acetate and 10% aqueous sodium carbonate of 240mL, stirring is added
Organic phase is collected in liquid separation after 15min.After organic phase anhydrous sodium sulfate drying, filtering.Filtrate decompression is concentrated to get oily liquids
31.8g is target product, yield 95.3%, purity 99.3%, ee 99.1%.
Step 5:
In the round-bottomed flask of 5000mL, the phthalic anhydride of substrate, that is, compound 5 of 167.8g and 109.8g is added
Enter into 1800mL toluene, 75.9g triethylamine is added dropwise.It is warming up to 90 degree of reactions, 2 hours or so monitoring end of reaction.It is cooled to room
1100mL 0.5M hydrochloric acid is added in temperature, stirs 30min, and organic phase is collected in liquid separation.Anhydrous sodium sulfate dries, filters, and collects female
Liquid is concentrated to dryness.Brown oil 246.0g is obtained, is cooled and solidified, yield 91.7%, purity 98.1%, ee
98.8%.
1H NMR (400MHz, CDCl3): δ=8.10 (d, 2H), 7.83-7.81 (m, 2H), 7.75-7.73 (m, 2H),
7.39(d,2H),5.20-5.17(m,1H),4.32-4.24(m,2H),3.73-3.64(m,2H),1.29(t,3H).
MS+:369.1
R isomers: in the round-bottomed flask of 1000mL, by substrate, that is, compound 5 of 31.0g and the O-phthalic of 19.3g
Acid anhydrides is added in 310mL toluene, and 13.1g triethylamine is added dropwise.It is warming up to 90 degree of reactions, 2 hours or so monitoring end of reaction.It is cold
But to room temperature, 190mL 0.5M hydrochloric acid is added, stirs 30min, organic phase is collected in liquid separation.Anhydrous sodium sulfate dries, filters, and receives
Collect mother liquor, is concentrated to dryness.Brown oil 42.5g is obtained, is cooled and solidified, yield 88.7%, purity 98.5%, ee
99.0%.
Step 6:
In the hydriding reactor of 2000mL, 10% palladium carbon of substrate, that is, compound 6 of 231.4g and 12.0g is added to
In the ethyl alcohol of 1440mL.Hydrogenation is warming up to 30 degree of reactions monitoring in 16 hours or so to end of reaction to 2.0MPa.It is cooled to room
Temperature, filtering, the ethanol washing of filter cake 240mL.Filtrate decompression is concentrated to get brown oil liquid, and cooling and solidifying obtains compound
7 be 215.7g, yield 100%, purity 98.8%, ee 98.9%.
1H NMR (400MHz, CDCl3): δ=7.80-7.78 (m, 2H), 7.71-7.69 (m, 2H), 6.96 (d, 2H),
6.53(d,2H),5.10-5.06(m,1H),4.28-4.23(m,2H),3.54(br,1H),3.51-3.44(m,2H),1.29
(t,3H)。
MS+:339.2
R isomers: in the hydriding reactor of 600mL, 10% palladium carbon of the substrate of 40.5g and 2.02g are added to 240mL's
In ethyl alcohol.Hydrogenation is warming up to 30 degree of reactions monitoring in 16 hours or so to end of reaction to 2.0MPa.It is cooled to room temperature, filters,
The ethanol washing of filter cake 40mL.Filtrate decompression is concentrated to get brown oil liquid, cooling and solidifying, 37.2g, and yield 100% is pure
Spend 99.0%, ee 99.2%.
Step 7:
In the round-bottomed flask of 5000mL, the ethylene oxide of substrate, that is, compound 7 of 204.2g and 286.3g is dissolved into
In the water of 1100mL and the acetic acid of 1100mL.Monitoring in 16 hours or so to raw material is stirred at room temperature to disappear.The second of 1000mL is added
Acetoacetic ester.After stirring 15 minutes, organic phase is collected in liquid separation.1100mL water washing is primary, 1100mL saturated sodium bicarbonate aqueous solution
It washed once, 1100mL water washing is primary.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids i.e. compound
8 be 217.5g, yield 85.1%, purity 99.1%, ee 99.1%.
1H NMR (400MHz, CDCl3): δ=7.79-7.77 (m, 2H), 7.70-7.68 (m, 2H), 7.01 (d, 2H),
6.52(d,2H),5.09-5.05(m,1H),4.28-4.22(m,2H),3.75-3.73(m,4H),3.50-3.40(m,6H),
1.29(t,3H).
MS+:427.2
R isomers: in the round-bottomed flask of 1000mL, the ethylene oxide of the substrate of 37.2g and 48.5g is dissolved into
In the water of 190mL and the acetic acid of 190mL.Monitoring in 16 hours or so to raw material is stirred at room temperature to disappear.The acetic acid second of 190mL is added
Ester.After stirring 15 minutes, organic phase is collected in liquid separation.190mL water washing is primary, 190mL saturated sodium bicarbonate aqueous solution washing one
Secondary, 190mL water washing is primary.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 41.4g, yield
88.3%, purity 98.5%, ee 99.0%.
Step 8:
In the round-bottomed flask of 5000mL, substrate, that is, compound 8 of 204.8g is mixed into the toluene of 2300mL, 0 degree
The phosphorus oxychloride of 253.0g is added dropwise.After being added dropwise, 70 degree of stirrings monitoring in 16 hours or so is heated to end of reaction.It depressurizes dense
It is reduced to and closely does, the ethyl acetate of 2300mL and the saturated aqueous sodium carbonate of 1150mL is added.After stirring 15 minutes, liquid separation is received
Collect organic phase.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 213.7g, yield 95.0%, purity
98.1%, ee99.0%.
1H NMR (400MHz, CDCl3): δ=7.83-7.80 (m, 2H), 7.73-7.71 (m, 2H), 7.07 (d, 2H),
6.52(d,2H),5.11-5.07(m,1H),4.30-4.22(m,2H),3.66-3.63(m,4H),3.56-3.47(m,6H),
1.29(t,3H).
MS+:463.1,464.2,465.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 38.4g is mixed into the toluene of 380mL, 0~10 degree
The phosphorus oxychloride of 41.4g is added dropwise.After being added dropwise, 70 degree of stirrings monitoring in 16 hours or so is heated to end of reaction.It depressurizes dense
It is reduced to and closely does, the ethyl acetate of 380mL and the saturated aqueous sodium carbonate of 190mL is added.After stirring 15 minutes, liquid separation is collected
Organic phase.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 40.5g, yield 97.1%, purity
98.5%, ee 99.3%.
Step 9:
In the round-bottomed flask of 3000mL, the substrate of 210.2g is mixed into 18% hydrochloric acid of 1440mL.It is heated to
100 degree monitor to end of reaction for stirring 16 hours or so.20 degree are cooled to, filtering.Mother liquor is collected, mother liquor is water-soluble using sodium acetate
Liquid adjusts pH to 6, and solid is precipitated, filtering, with the water washing filter cake of 1200mL.Filter cake is collected, it is solid to obtain off-white color for filter cake drying
Body 119.8g, yield 85.0%, purity 99.0%, ee 99.1%.
1H NMR (400MHz, CDCl3): δ=7.14 (d, 2H), 6.66 (d, 2H), 3.69 (s, 8H), 3.44-3.41 (m,
1H),3.05-3.00(m,1H),2.85-2.79(m,1H).
MS+:305.1,307.1,308.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 39.4g is mixed into 18% hydrochloric acid of 240mL.Add
Heat is stirred 16 hours or so to 100 degree and is monitored to end of reaction.20 degree are cooled to, filtering.Mother liquor is collected, mother liquor uses sodium acetate
Aqueous solution adjusts pH to 6, and solid is precipitated, filtering, with the water washing filter cake of 200mL.Filter cake is collected, it is white to obtain class for filter cake drying
Color solid 21.5g, yield 82.9%, purity 99.3%, ee 99.2%.
Embodiment 2:
A kind of Melphalan intermediate the preparation method is as follows:
Step 1:
In the round-bottomed flask of 2L, the paranitrobenzaldehyde of 181.2g is added in the methylene chloride of 2L, is added
2- acetylaminohydroxyphenylarsonic acid 2- (dimethoxyphosphoryl) methyl acetate of 344.4g.In 3 DEG C of dropwise addition 237.4g DBU, after dripping, instead
Monitoring in 2 hours or so to raw material is answered to disappear.5% aqueous sulfuric acid of 900mL, filtering is added dropwise, filter cake is eluted with the water of 450mL.It receives
Collect filter cake.Yellow solid 311.7g, as target product are obtained after filter cake drying.Yield 98.8%, purity 98.9%.
1H NMR (400MHz, CDCl3): δ=8.23 (d, 2H), 7.57 (d, 2H), 7.42 (d, 2H), 3.92 (s, 2H),
2.16(s,3H).
MS+:265.1
Step 2:
In the hydriding reactor of 2000mL, the substrate of 237.9g and 145mg Rh (ScRp-DuanPhos) (NBD) BF4 are added
Enter into the methanol of 1200mL.Under 0.5~1.0MPa Hydrogen Vapor Pressure, 20 degree of reactions monitoring in 6 hours or so to raw material disappears.Body
System's reduced pressure is dry to obtain yellow solid 239.9g, is target product.Yield 100%, purity 98.6%, ee 99.7%.
1H NMR (400MHz, CDCl3): δ=8.17 (d, 2H), 7.31 (d, 2H), 6.07 (d, 1H), 4.97 (q, 1H),
3.76(s,1H),3.34(dd,1H),3.22(dd,1H),2.02(s,1H).
MS+:267.1
[α]=23 (1g/100mL methanol, 20 degree)
R isomers: in the hydriding reactor of 600mL, by the upper step product and 28.2mg Rh (RcSp-DuanPhos) of 44.9g
(NBD) BF4 is added in the methanol of 225mL.Under 0.8MPa Hydrogen Vapor Pressure, 20 degree of reactions, 6 hours or so monitoring to raw materials disappear
It loses.System reduced pressure is dry to obtain yellow solid 45.3g, is target product.Yield 100%, purity 98.7%, ee 99.8%.
Step 3:
In the round-bottomed flask of 2L, the substrate of 237.0g is added in 6% hydrochloric acid of 900mL.It is small in 100 degree of reactions 20
When or so monitoring to raw material disappear.System is cooled to room temperature, and filter cake is collected in filtering.Filter cake dries to obtain yellow solid 202.0g,
For target product.Yield 92.0%, purity 99.3%, ee99.8%.
1H NMR (400MHz, D2O): δ=8.05 (d, 2H), 7.40 (d, 2H), 4.34 (q, 1H), 3.35 (dd, 1H),
3.26(dd,1H).
MS+:211.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 44.7g is added in 6% hydrochloric acid of 170mL.100
Degree reaction monitoring in 20 hours or so to raw material disappears.System is cooled to room temperature, and filter cake is collected in filtering.Filter cake dries to obtain yellow
Solid 37.6g is target product.Yield 92.0%, purity 99.1%, ee 99.4%.
Step 4:
In the round-bottomed flask of 2000mL, the substrate of 197.3g is added in the dehydrated alcohol of 1400mL.It is added dropwise at 6 degree
190.4g thionyl chloride.After being added dropwise, it is warming up to 60 degree of reactions monitoring in 15 hours or so to raw material and disappears.System is cooled to room
Temperature is concentrated under reduced pressure into close dry.1400mL ethyl acetate and 10% aqueous sodium carbonate of 1400mL is added, divides after stirring 15min
Liquid collects organic phase.After organic phase anhydrous sodium sulfate drying, filtering.Filtrate decompression is concentrated to get oily liquids 187.8g, is
Target product, yield 98.5%, purity 99.1%, ee 99.3%.
1H NMR (400MHz, CDCl3): δ=8.18 (d, 2H), 7.41 (d, 2H), 4.20 (q, 2H), 3.76 (t, 1H),
3.20(dd,1H),3.00(dd,1H),1.27(t,3H).
MS+:239.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 34.5g is added in the dehydrated alcohol of 240mL.6
33.3g thionyl chloride is added dropwise in degree.After being added dropwise, it is warming up to 60 degree of reactions monitoring in 15 hours or so to raw material and disappears.System is cold
But it to room temperature, is concentrated under reduced pressure into close dry.240mL ethyl acetate and 10% aqueous sodium carbonate of 240mL is added, after stirring 15min
Organic phase is collected in liquid separation.After organic phase anhydrous sodium sulfate drying, filtering.Filtrate decompression is concentrated to get oily liquids 31.8g,
For target product, yield 95.3%, purity 99.3%, ee 99.1%.
Step 5:
In the round-bottomed flask of 5000mL, the phthalic anhydride of the substrate of 178.7g and 111.1g is added to 1800mL
In toluene, 75.9g triethylamine is added dropwise.It is warming up to 90 degree of reactions, 2 hours or so monitoring end of reaction.It is cooled to room temperature, is added
1100mL 0.5M hydrochloric acid, stirs 30min, and organic phase is collected in liquid separation.Anhydrous sodium sulfate dries, filters, and collects mother liquor, depressurizes dense
It is reduced to dry.Brown oil 254.0g is obtained, is cooled and solidified, yield 91.9%, purity 98.2%, ee 99.0%.
1H NMR (400MHz, CDCl3): δ=8.10 (d, 2H), 7.83-7.81 (m, 2H), 7.75-7.73 (m, 2H),
7.39(d,2H),5.20-5.17(m,1H),4.32-4.24(m,2H),3.73-3.64(m,2H),1.29(t,3H).
MS+:369.1
R isomers: in the round-bottomed flask of 1000mL, the phthalic anhydride of the substrate of 31.0g and 19.3g is added to
In 310mL toluene, 13.1g triethylamine is added dropwise.It is warming up to 90 degree of reactions, 2 hours or so monitoring end of reaction.It is cooled to room temperature, adds
Enter 190mL 0.5M hydrochloric acid, stir 30min, organic phase is collected in liquid separation.Anhydrous sodium sulfate dries, filters, and collects mother liquor, decompression
It is concentrated to dryness.Brown oil 42.5g is obtained, is cooled and solidified, yield 88.7%, purity 98.5%, ee 99.0%.
Step 6:
In the hydriding reactor of 2000mL, 10% palladium carbon of the substrate of 239.4g and 12.0g is added to the ethyl alcohol of 1440mL
In.Hydrogenation is warming up to 30 degree of reactions monitoring in 16 hours or so to end of reaction to 2.0MPa.It is cooled to room temperature, filters, filter cake
With the ethanol washing of 240mL.Filtrate decompression is concentrated to get brown oil liquid, cooling and solidifying, 220.0g, yield 100%, purity
99.0%, ee 99.0%.
1H NMR (400MHz, CDCl3): δ=7.80-7.78 (m, 2H), 7.71-7.69 (m, 2H), 6.96 (d, 2H),
6.53(d,2H),5.10-5.06(m,1H),4.28-4.23(m,2H),3.54(br,1H),3.51-3.44(m,2H),1.29
(t,3H).
MS+:339.2
R isomers: in the hydriding reactor of 600mL, 10% palladium carbon of the substrate of 40.5g and 2.02g are added to 240mL's
In ethyl alcohol.Hydrogenation is warming up to 30 degree of reactions monitoring in 16 hours or so to end of reaction to 2.0MPa.It is cooled to room temperature, filters,
The ethanol washing of filter cake 40mL.Filtrate decompression is concentrated to get brown oil liquid, cooling and solidifying, 37.2g, and yield 100% is pure
Spend 99.0%, ee 99.2%.
Step 7:
In the round-bottomed flask of 5000mL, the ethylene oxide of the substrate of 220.0g and 286.3g is dissolved into the water of 1100mL
And in the acetic acid of 1100mL.Monitoring in 16 hours or so to raw material is stirred at room temperature to disappear.The ethyl acetate of 1000mL is added.Stirring
After 15 minutes, organic phase is collected in liquid separation.1100mL water washing is primary, and 1100mL saturated sodium bicarbonate aqueous solution washed once,
1100mL water washing is primary.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 236.1g, yield
85.1%, purity 99.1%, ee 99.2%.
1H NMR (400MHz, CDCl3): δ=7.79-7.77 (m, 2H), 7.70-7.68 (m, 2H), 7.01 (d, 2H),
6.52(d,2H),5.09-5.05(m,1H),4.28-4.22(m,2H),3.75-3.73(m,4H),3.50-3.40(m,6H),
1.29(t,3H).
MS+:427.2
R isomers: in the round-bottomed flask of 1000mL, the ethylene oxide of the substrate of 37.2g and 48.5g is dissolved into
In the water of 190mL and the acetic acid of 190mL.Monitoring in 16 hours or so to raw material is stirred at room temperature to disappear.The acetic acid second of 190mL is added
Ester.After stirring 15 minutes, organic phase is collected in liquid separation.190mL water washing is primary, 190mL saturated sodium bicarbonate aqueous solution washing one
Secondary, 190mL water washing is primary.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 41.4g, yield
88.3%, purity 98.5%, ee 99.0%.
Step 8:
In the round-bottomed flask of 5000mL, the substrate of 234.6g is mixed into the toluene of 2300mL, 0~10 degree of dropwise addition
The phosphorus oxychloride of 253.0g.After being added dropwise, 70 degree of stirrings monitoring in 16 hours or so is heated to end of reaction.It is concentrated under reduced pressure into
It is close dry, the ethyl acetate of 2300mL and the saturated aqueous sodium carbonate of 1150mL is added.After stirring 15 minutes, liquid separation, collection has
Machine phase.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 242.6g, yield 95.2%, purity 98.3%,
Ee 99.1%.
1H NMR (400MHz, CDCl3): δ=7.83-7.80 (m, 2H), 7.73-7.71 (m, 2H), 7.07 (d, 2H),
6.52(d,2H),5.11-5.07(m,1H),4.30-4.22(m,2H),3.66-3.63(m,4H),3.56-3.47(m,6H),
1.29(t,3H).
MS+:463.1,464.2,465.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 38.4g is mixed into the toluene of 380mL, 0~10 degree
The phosphorus oxychloride of 41.4g is added dropwise.After being added dropwise, 70 degree of stirrings monitoring in 16 hours or so is heated to end of reaction.It depressurizes dense
It is reduced to and closely does, the ethyl acetate of 380mL and the saturated aqueous sodium carbonate of 190mL is added.After stirring 15 minutes, liquid separation is collected
Organic phase.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 40.5g, yield 97.1%, purity
98.5%, ee 99.3%.
Step 9:
In the round-bottomed flask of 3000mL, the substrate of 240.9g is mixed into 18% hydrochloric acid of 1440mL.It is heated to
100 degree monitor to end of reaction for stirring 16 hours or so.20 degree are cooled to, filtering.Mother liquor is collected, mother liquor is water-soluble using sodium acetate
Liquid adjusts pH to 6, and solid is precipitated, filtering, with the water washing filter cake of 1200mL.Filter cake is collected, it is solid to obtain off-white color for filter cake drying
Body 135.3g, yield 85.2%, purity 99.1%, ee 99.3%.
1H NMR (400MHz, CDCl3): δ=7.14 (d, 2H), 6.66 (d, 2H), 3.69 (s, 8H), 3.44-3.41 (m,
1H),3.05-3.00(m,1H),2.85-2.79(m,1H).
MS+:305.1,307.1,308.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 39.4g is mixed into 18% hydrochloric acid of 240mL.Add
Heat is stirred 16 hours or so to 100 degree and is monitored to end of reaction.20 degree are cooled to, filtering.Mother liquor is collected, mother liquor uses sodium acetate
Aqueous solution adjusts pH to 6, and solid is precipitated, filtering, with the water washing filter cake of 200mL.Filter cake is collected, it is white to obtain class for filter cake drying
Color solid 21.5g, yield 82.9%, purity 99.3%, ee 99.2%.
Embodiment 3:
A kind of Melphalan intermediate the preparation method is as follows:
Step 1:
In the round-bottomed flask of 2L, the paranitrobenzaldehyde of 190.5g is added in the methylene chloride of 2L, is added
2- acetylaminohydroxyphenylarsonic acid 2- (dimethoxyphosphoryl) methyl acetate of 344.4g.In 5 DEG C of dropwise addition 237.4g DBU, after dripping, instead
Monitoring in 2 hours or so to raw material is answered to disappear.5% aqueous sulfuric acid of 900mL, filtering is added dropwise, filter cake is eluted with the water of 450mL.It receives
Collect filter cake.Yellow solid 317.5g is obtained after filter cake drying, as target product, that is, compound 2.Yield 98.9%, purity
99.2%.
1H NMR (400MHz, CDCl3): δ=8.23 (d, 2H), 7.57 (d, 2H), 7.42 (d, 2H), 3.92 (s, 2H),
2.16(s,3H).
MS+:265.1
Step 2:
In the hydriding reactor of 2000mL, the substrate of 241.2g and 145mg Rh (ScRp-DuanPhos) (NBD) BF4 are added
Enter into the methanol of 1200mL.Under 1.0MPa Hydrogen Vapor Pressure, 20 degree of reactions monitoring in 6 hours or so to raw material disappears.System subtracts
Pressure concentration is dry to obtain yellow solid 246.3g, is target product.Yield 100%, purity 98.8%, ee 99.8%.
1H NMR (400MHz, CDCl3): δ=8.17 (d, 2H), 7.31 (d, 2H), 6.07 (d, 1H), 4.97 (q, 1H),
3.76(s,1H),3.34(dd,1H),3.22(dd,1H),2.02(s,1H).
MS+:267.1
[α]=23 (1g/100mL methanol, 20 degree)
R isomers: in the hydriding reactor of 600mL, by the upper step product and 28.2mg Rh (RcSp-DuanPhos) of 44.9g
(NBD) BF4 is added in the methanol of 225mL.Under 1.0MPa Hydrogen Vapor Pressure, 20 degree of reactions, 6 hours or so monitoring to raw materials disappear
It loses.System reduced pressure is dry to obtain yellow solid 45.3g, is target product.Yield 100%, purity 98.7%, ee 99.8%.
Step 3:
In the round-bottomed flask of 2L, the substrate of 241.3.0g is added in 6% hydrochloric acid of 900mL.20 are reacted at 100 degree
Or so hour monitoring to raw material disappears.System is cooled to room temperature, and filter cake is collected in filtering.Filter cake dries to obtain yellow solid
202.0g being target product.Yield 92.2%, purity 99.4%, ee 99.8%.
1H NMR (400MHz, D2O): δ=8.05 (d, 2H), 7.40 (d, 2H), 4.34 (q, 1H), 3.35 (dd, 1H),
3.26(dd,1H).
MS+:211.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 44.7g is added in 6% hydrochloric acid of 170mL.100
Degree reaction monitoring in 20 hours or so to raw material disappears.System is cooled to room temperature, and filter cake is collected in filtering.Filter cake dries to obtain yellow
Solid 37.6g is target product.Yield 92.0%, purity 99.1%, ee 99.4%.
Step 4:
In the round-bottomed flask of 2000mL, substrate, that is, compound 4 of 203.5g is added in the dehydrated alcohol of 1400mL.
In 10 degree of dropwise addition 190.4g thionyl chlorides.After being added dropwise, it is warming up to 60 degree of reactions monitoring in 15 hours or so to raw material and disappears.Body
System is cooled to room temperature, and is concentrated under reduced pressure into close dry.1400mL ethyl acetate and 10% aqueous sodium carbonate of 1400mL, stirring is added
Organic phase is collected in liquid separation after 15min.After organic phase anhydrous sodium sulfate drying, filtering.Filtrate decompression is concentrated to get oily liquids
190.2g is target product, that is, compound 5, yield 98.7%, purity 99.2%, ee 99.4%.
1H NMR (400MHz, CDCl3): δ=8.18 (d, 2H), 7.41 (d, 2H), 4.20 (q, 2H), 3.76 (t, 1H),
3.20(dd,1H),3.00(dd,1H),1.27(t,3H).
MS+:239.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 34.5g is added in the dehydrated alcohol of 240mL.0
~10 degree of dropwise addition 33.3g thionyl chlorides.After being added dropwise, it is warming up to 60 degree of reactions monitoring in 15 hours or so to raw material and disappears.Body
System is cooled to room temperature, and is concentrated under reduced pressure into close dry.240mL ethyl acetate and 10% aqueous sodium carbonate of 240mL, stirring is added
Organic phase is collected in liquid separation after 15min.After organic phase anhydrous sodium sulfate drying, filtering.Filtrate decompression is concentrated to get oily liquids
31.8g is target product, yield 95.3%, purity 99.3%, ee 99.1%.
Step 5:
In the round-bottomed flask of 5000mL, the phthalic anhydride of substrate, that is, compound 5 of 185.3g and 111.1g is added
Enter into 1800mL toluene, 75.9g triethylamine is added dropwise.It is warming up to 90 degree of reactions, 2 hours or so monitoring end of reaction.It is cooled to room
1100mL 0.5M hydrochloric acid is added in temperature, stirs 30min, and organic phase is collected in liquid separation.Anhydrous sodium sulfate dries, filters, and collects female
Liquid is concentrated to dryness.Brown oil 261.3g is obtained, is cooled and solidified, yield 92.3%, purity 98.5%, ee
99.2%.
1H NMR (400MHz, CDCl3): δ=8.10 (d, 2H), 7.83-7.81 (m, 2H), 7.75-7.73 (m, 2H),
7.39(d,2H),5.20-5.17(m,1H),4.32-4.24(m,2H),3.73-3.64(m,2H),1.29(t,3H).
MS+:369.1
R isomers: in the round-bottomed flask of 1000mL, the phthalic anhydride of the substrate of 31.0g and 19.3g is added to
In 310mL toluene, 13.1g triethylamine is added dropwise.It is warming up to 90 degree of reactions, 2 hours or so monitoring end of reaction.It is cooled to room temperature, adds
Enter 190mL 0.5M hydrochloric acid, stir 30min, organic phase is collected in liquid separation.Anhydrous sodium sulfate dries, filters, and collects mother liquor, decompression
It is concentrated to dryness.Brown oil 42.5g is obtained, is cooled and solidified, yield 88.7%, purity 98.5%, ee 99.0%.
Step 6:
In the hydriding reactor of 2000mL, 10% palladium carbon of the substrate of 246.7g and 12.0g is added to the ethyl alcohol of 1440mL
In.Hydrogenation is warming up to 30 degree of reactions monitoring in 16 hours or so to end of reaction to 2.0MPa.It is cooled to room temperature, filters, filter cake
With the ethanol washing of 240mL.Filtrate decompression is concentrated to get brown oil liquid, and it is 234.7g that cooling and solidifying, which obtains compound 7, receives
Rate 100%, purity 99.2%, ee 99.3%.
1H NMR (400MHz, CDCl3): δ=7.80-7.78 (m, 2H), 7.71-7.69 (m, 2H), 6.96 (d, 2H),
6.53(d,2H),5.10-5.06(m,1H),4.28-4.23(m,2H),3.54(br,1H),3.51-3.44(m,2H),1.29
(t,3H).
MS+:339.2
R isomers: in the hydriding reactor of 600mL, 10% palladium carbon of the substrate of 40.5g and 2.02g are added to 240mL's
In ethyl alcohol.Hydrogenation is warming up to 30 degree of reactions monitoring in 16 hours or so to end of reaction to 2.0MPa.It is cooled to room temperature, filters,
The ethanol washing of filter cake 40mL.Filtrate decompression is concentrated to get brown oil liquid, cooling and solidifying, 37.2g, and yield 100% is pure
Spend 99.0%, ee 99.2%.
Step 7:
In the round-bottomed flask of 5000mL, the ethylene oxide of substrate, that is, compound 7 of 230.0g and 286.3g is dissolved into
In the water of 1100mL and the acetic acid of 1100mL.Monitoring in 16 hours or so to raw material is stirred at room temperature to disappear.The second of 1000mL is added
Acetoacetic ester.After stirring 15 minutes, organic phase is collected in liquid separation.1100mL water washing is primary, 1100mL saturated sodium bicarbonate aqueous solution
It washed once, 1100mL water washing is primary.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 248.6g,
Yield 85.3%, purity 99.2%, ee 99.3%.
1H NMR (400MHz, CDCl3): δ=7.79-7.77 (m, 2H), 7.70-7.68 (m, 2H), 7.01 (d, 2H),
6.52(d,2H),5.09-5.05(m,1H),4.28-4.22(m,2H),3.75-3.73(m,4H),3.50-3.40(m,6H),
1.29(t,3H).
MS+:427.2
R isomers: in the round-bottomed flask of 1000mL, the ethylene oxide of the substrate of 37.2g and 48.5g is dissolved into
In the water of 190mL and the acetic acid of 190mL.Monitoring in 16 hours or so to raw material is stirred at room temperature to disappear.The acetic acid second of 190mL is added
Ester.After stirring 15 minutes, organic phase is collected in liquid separation.190mL water washing is primary, 190mL saturated sodium bicarbonate aqueous solution washing one
Secondary, 190mL water washing is primary.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 41.4g, yield
88.3%, purity 98.5%, ee 99.0%.
Step 8:
In the round-bottomed flask of 5000mL, the substrate of 247.6g is mixed into the toluene of 2300mL, 10 degree of dropwise additions
The phosphorus oxychloride of 253.0g.After being added dropwise, 70 degree of stirrings monitoring in 16 hours or so is heated to end of reaction.It is concentrated under reduced pressure into
It is close dry, the ethyl acetate of 2300mL and the saturated aqueous sodium carbonate of 1150mL is added.After stirring 15 minutes, liquid separation, collection has
Machine phase.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 251.2g, yield 95.3%, purity 98.5%,
Ee 99.2%.
1H NMR (400MHz, CDCl3): δ=7.83-7.80 (m, 2H), 7.73-7.71 (m, 2H), 7.07 (d, 2H),
6.52(d,2H),5.11-5.07(m,1H),4.30-4.22(m,2H),3.66-3.63(m,4H),3.56-3.47(m,6H),
1.29(t,3H).
MS+:463.1,464.2,465.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 38.4g is mixed into the toluene of 380mL, 0~10 degree
The phosphorus oxychloride of 41.4g is added dropwise.After being added dropwise, 70 degree of stirrings monitoring in 16 hours or so is heated to end of reaction.It depressurizes dense
It is reduced to and closely does, the ethyl acetate of 380mL and the saturated aqueous sodium carbonate of 190mL is added.After stirring 15 minutes, liquid separation is collected
Organic phase.Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give oily liquids 40.5g, yield 97.1%, purity
98.5%, ee 99.3%.
Step 9:
In the round-bottomed flask of 3000mL, the substrate of 250.2g is mixed into 18% hydrochloric acid of 1440mL.It is heated to
100 degree monitor to end of reaction for stirring 16 hours or so.20 degree are cooled to, filtering.Mother liquor is collected, mother liquor is water-soluble using sodium acetate
Liquid adjusts pH to 6, and solid is precipitated, filtering, with the water washing filter cake of 1200mL.Filter cake is collected, it is solid to obtain off-white color for filter cake drying
Body 140.2g, yield 85.3%, purity 99.2%, ee 99.4%.
1H NMR (400MHz, CDCl3): δ=7.14 (d, 2H), 6.66 (d, 2H), 3.69 (s, 8H), 3.44-3.41 (m,
1H),3.05-3.00(m,1H),2.85-2.79(m,1H).
MS+:305.1,307.1,308.1
R isomers: in the round-bottomed flask of 500mL, the substrate of 39.4g is mixed into 18% hydrochloric acid of 240mL.Add
Heat is stirred 16 hours or so to 100 degree and is monitored to end of reaction.20 degree are cooled to, filtering.Mother liquor is collected, mother liquor uses sodium acetate
Aqueous solution adjusts pH to 6, and solid is precipitated, filtering, with the water washing filter cake of 200mL.Filter cake is collected, it is white to obtain class for filter cake drying
Color solid 21.5g, yield 82.9%, purity 99.3%, ee 99.2%.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (4)
1. a kind of Melphalan intermediate, it is characterised in that the Melphalan midbody compound structural formula such as formula 10:
2. a kind of preparation method of Melphalan intermediate as described in claim 1, it is characterised in that the method is as follows:
Step1:
It is that paranitrobenzaldehyde is added in the mixed liquor of methylene chloride DCM, and 2- acetylaminohydroxyphenylarsonic acid 2- (diformazan is added by compound 1
Oxygroup phosphoryl) methyl acetate, reacts to raw material in 0~5 DEG C of dropwise addition DBU and disappears；It is filtered after 5% aqueous sulfuric acid is added dropwise, it will
Compound 2 is obtained after filter cake drying, synthetic route is as follows:
Step2:
In hydriding reactor, compound 2 described in Step1 and Rh (ScRp-DuanPhos) (NBD) BF4 are added in methanol；?
Under 0.5~1.0MPa Hydrogen Vapor Pressure, 20 DEG C of reactions to raw material disappear；System is concentrated under reduced pressure to give compound 3, and synthetic route is such as
Under:
Step3:
In 6% hydrochloric acid that compound 3 described in Step2 is added to；It disappears in 100 DEG C of reactions to raw material；System is cooled to room temperature
After filter, filter cake is dried to obtain compound 4, synthetic route is as follows:
Step4:
Compound 4 described in Step3 is added in dehydrated alcohol；In 0~10 DEG C of dropwise addition thionyl chloride；Be warming up to 60 degree react to
Raw material disappears；System is cooled to room temperature, and is concentrated under reduced pressure；Ethyl acetate and 10% aqueous sodium carbonate is added, divides after mixing evenly
Liquid collects organic phase；After organic phase anhydrous sodium sulfate drying, filtering；Filtrate decompression is concentrated to get compound 5, synthetic route
It is as follows:
Step5:
Compound 5 and phthalic anhydride described in Step4 are added in toluene, triethylamine is added dropwise；90 degree are warming up to reaction
It finishes；It is cooled to room temperature, 0.5M hydrochloric acid is added, stir liquid separation, collect organic phase；Organic phase is dry using anhydrous sodium sulfate, mistake
Mother liquor is collected in filter, is concentrated under reduced pressure to give compound 6, synthetic route is as follows:
Step6:
In hydriding reactor, compound 6 described in Step5 and 10% palladium carbon are added in ethyl alcohol；Hydrogenation is warming up to 2.0MPa
30 degree to end of reaction；It is cooled to room temperature, filters；Filtrate decompression is concentrated to get compound 7, and synthetic route is as follows:
Step7:
Compound 7 and ethylene oxide described in Step6 are dissolved into water and acetic acid；It is stirred at room temperature to raw material and is disappeared；Second is added
Acetoacetic ester, stirring, collect organic phase at liquid separation；Organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure to give compound 8, synthesizes road
Line is as follows:
Step8:
Compound 8 described in Step7 is mixed into toluene, 0~10 DEG C of dropwise addition phosphorus oxychloride；70 DEG C of stirrings are heated to having reacted
Finish；It is concentrated under reduced pressure, adds ethyl acetate and saturated aqueous sodium carbonate, stirring, collects organic phase at liquid separation；The anhydrous sulphur of organic phase
Sour sodium is dry, is concentrated under reduced pressure to give compound 9, synthetic route is as follows:
Step9:
Compound 9 described in Step8 is mixed into 18% hydrochloric acid；100 DEG C of stirrings are heated to end of reaction；It is cooled to 20
Degree filters, collects mother liquor, and mother liquor adjusts pH to 6 using sodium acetate aqueous solution, and solid is precipitated, filters, obtains after filter cake is dried
Compound 10, synthetic route is as follows:
3. a kind of preparation method of Melphalan intermediate according to claim 2, it is characterised in that filtered described in Step1
Cake is eluted before drying with water.
4. a kind of preparation method of Melphalan intermediate according to claim 2, it is characterised in that have described in Step7
Machine is mutually before the drying successively using water washing is primary, saturated sodium bicarbonate aqueous solution washed once, water washing is primary.
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| CN114315618A (en) * | 2021-12-04 | 2022-04-12 | 浙江恒腾福生物科技集团有限公司 | Preparation method of synthetic melphalan |
| CN114524741A (en) * | 2022-02-15 | 2022-05-24 | 上海龙翔生物医药开发有限公司 | Synthesis process of antitumor drug melphalan |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101100440A (en) * | 2007-04-20 | 2008-01-09 | 苏州市立德化学有限公司 | Technique for synthesizing antineoplastic melphalan |
| CN102030671A (en) * | 2010-10-26 | 2011-04-27 | 浙江凯普化工有限公司 | Preparing method of pharmaceutical melphalam, and hydrochloride and dihydrochloride of pharmaceutical melphalam |
| US20120190887A1 (en) * | 2008-02-21 | 2012-07-26 | Chen Zhou | Processes for preparing pharmaceutical grade melphalans from industrial grade reactants |
| CN105198775A (en) * | 2015-10-10 | 2015-12-30 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of chiral N-Boc biphenyl alaninol |
| CN106083693A (en) * | 2016-06-14 | 2016-11-09 | 王健 | The N phthalyl synthesis technique to (dihydroxy ethyl) amino L phenylalanine ethyl ester |
-
2019
- 2019-05-06 CN CN201910369683.0A patent/CN110041214A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101100440A (en) * | 2007-04-20 | 2008-01-09 | 苏州市立德化学有限公司 | Technique for synthesizing antineoplastic melphalan |
| US20120190887A1 (en) * | 2008-02-21 | 2012-07-26 | Chen Zhou | Processes for preparing pharmaceutical grade melphalans from industrial grade reactants |
| CN102030671A (en) * | 2010-10-26 | 2011-04-27 | 浙江凯普化工有限公司 | Preparing method of pharmaceutical melphalam, and hydrochloride and dihydrochloride of pharmaceutical melphalam |
| CN105198775A (en) * | 2015-10-10 | 2015-12-30 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of chiral N-Boc biphenyl alaninol |
| CN106083693A (en) * | 2016-06-14 | 2016-11-09 | 王健 | The N phthalyl synthesis technique to (dihydroxy ethyl) amino L phenylalanine ethyl ester |
Non-Patent Citations (2)
| Title |
|---|
| VIVEKANANDA M. VRUDHULA，等: "Prodrugs of doxorubicin and melphalan and their activation by a monoclonal antibody-penicillin-G amidase conjugate", 《J. MED. CHEM.》 * |
| 张娜，等: "美法仑衍生物的合成及其抗肿瘤活性研究", 《现代药物与临床》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315618A (en) * | 2021-12-04 | 2022-04-12 | 浙江恒腾福生物科技集团有限公司 | Preparation method of synthetic melphalan |
| CN114524741A (en) * | 2022-02-15 | 2022-05-24 | 上海龙翔生物医药开发有限公司 | Synthesis process of antitumor drug melphalan |
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