CN110483363A - A kind of preparation method of tryptophan esters hydrochloride - Google Patents
A kind of preparation method of tryptophan esters hydrochloride Download PDFInfo
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- CN110483363A CN110483363A CN201910721853.7A CN201910721853A CN110483363A CN 110483363 A CN110483363 A CN 110483363A CN 201910721853 A CN201910721853 A CN 201910721853A CN 110483363 A CN110483363 A CN 110483363A
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- tryptophan
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- hydrochloride
- alcohol
- esters hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of preparation methods of tryptophan esters hydrochloride.The preparation method of this tryptophan esters hydrochloride, comprising the following steps: 1) paratoluensulfonyl chloride and tryptophan are reacted in alcohol, obtain tryptophan ester hydrochloride crude product;2) tryptophan ester hydrochloride crude product is purified, tryptophan esters hydrochloride is obtained.The method that the present invention prepares tryptophan esters hydrochloride is easy to get using market and cheap paratoluensulfonyl chloride, lower alcohol are as raw material, reaction condition is easily achieved, easy to operate, and cost is substantially reduced with respect to other methods, obtained product purity is high, is suitble to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation methods of tryptophan esters hydrochloride.
Background technique
L-Trp methyl ester hydrochloride is tetrahydro-beta-carboline diketopiperazine compound, such compound has good
Antibacterial activity, anti-tumor activity and molecular structure complicated and changeable, are with a wide range of applications in terms of drug development.Mesh
Before, many tetrahydro-beta-carboline class compounds are already used to treat a variety of diseases, such as cancer, tumour, AIDS, male erectile
Dysfunction, anti-inflammatory analgesic and viral disease and communicable disease.D-trp methyl ester hydrochloride is tadalafil synthesis
Important source material, for treating male erectile dysfunction (MED).
The preparation method of currently used tryptophan methyl ester hydrochloride include proton acid system (hydrogen chloride gas, to toluene sulphur
Acid etc.) and thionyl chloride method etc..The common hydrogen chloride of proton acid system and p-methyl benzenesulfonic acid, gas chlorination hydrogen additional amount be not easily-controllable
System, gas leak will cause air pollution, and transport and preservation all have safety problem.P-methyl benzenesulfonic acid method reaction time length and nothing
Method directly synthesizes ester hydrochloride, and post-processing is complicated, and yield is bad.For thionyl chloride method since thionyl chloride activity is high, reaction is violent,
Low-temperature operation is needed, it is at high cost, limit its industrial value.
Although above-mentioned these preparation methods obtain certain popularization and use, however it remains some disadvantages, including cumbersome
The problems such as transport and preservation of operation, harsh reaction condition and raw material.
Summary of the invention
Of the existing technology in order to overcome the problems, such as, the purpose of the present invention is to provide a kind of tryptophan esters hydrochlorides
Preparation method.
The technical solution used in the present invention is:
A kind of preparation method of tryptophan esters hydrochloride, comprising the following steps:
1) paratoluensulfonyl chloride and tryptophan are reacted in alcohol, obtains tryptophan ester hydrochloride crude product;
2) tryptophan ester hydrochloride crude product is purified, tryptophan esters hydrochloride is obtained.
Preferably, in the preparation method step 1) of this tryptophan esters hydrochloride, paratoluensulfonyl chloride, tryptophan and alcohol
Dosage be 1g:(0.1~2) g:(10~100) mL;It is further preferred that the mass ratio of paratoluensulfonyl chloride and tryptophan is
1:(0.1~1);The amount ratio of paratoluensulfonyl chloride and alcohol is 1g:(12~60) mL.
Preferably, in the preparation method step 1) of this tryptophan esters hydrochloride, tryptophan be selected from L-Trp or
One or both of D-trp.
It preferably, further include the step of the extra alcohol of removal in the preparation method step 1) of this tryptophan esters hydrochloride
Suddenly, specifically after having reacted, tryptophan ester hydrochloride crude product is precipitated in removal alcohol.
Preferably, in the preparation method step 1) of this tryptophan esters hydrochloride, remove alcohol method be rotary evaporation,
Volatilization, vacuum distillation in any one;It is further preferred that the method for removal alcohol is rotary evaporation.
Preferably, in the preparation method step 1) of this tryptophan esters hydrochloride, alcohol is selected from C1~C10 alcohol;Further
Preferably, alcohol is selected from C1~C4 alcohol;Still further preferably, alcohol is selected from the monohydric alcohol of C1~C4;Still more preferably, alcohol selects
From at least one of methanol, ethyl alcohol, normal propyl alcohol, n-butanol.
Preferably, in the preparation method step 1) of this tryptophan esters hydrochloride, the temperature of reaction is room temperature~130
DEG C, the time of reaction is 4h~20h.Room temperature in reaction condition of the present invention generally refers to 10 DEG C~25 DEG C.
Preferably, in the preparation method step 2) of this tryptophan esters hydrochloride, purification is specifically by tryptophan ester salt
Hydrochlorate crude product and organic solvent mixing are added pH that lye adjusts mixed liquor to alkalinity, then extract organic phase and mixed in hydrochloric acid,
Filtering, obtains tryptophan esters hydrochloride.
Preferably, in purification described in the preparation method step 2) of this tryptophan esters hydrochloride, lye is alkali metal
At least one of hydroxide aqueous solution, aqueous alkali carbonate solution, alkali metal hydrogencarbonate aqueous solution;Further preferably
, lye is at least one of sodium hydrate aqueous solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, wet chemical;
The mass concentration of lye can be 5%~20%.
Preferably, in purification described in the preparation method step 2) of this tryptophan esters hydrochloride, mixed liquor is adjusted
PH refers to alkalinity adjusts pH value to 8~11.
Preferably, in purification described in the preparation method step 2) of this tryptophan esters hydrochloride, organic solvent is ester
Class solvent, ketones solvent, ether solvent, amide solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, in nitrile solvents extremely
Few one kind;It is further preferred that organic solvent is ethyl acetate, acetone, ether, petroleum ether, dimethylformamide, dichloromethane
At least one of alkane, chloroform, carbon tetrachloride, toluene, dimethylbenzene, acetonitrile;Still further preferably, organic solvent is acetic acid second
At least one of ester, ether, methylene chloride, chloroform, carbon tetrachloride.
Preferably, in purification described in the preparation method step 2) of this tryptophan esters hydrochloride, organic phase and hydrochloric acid
It mixes muddy to occurring;It is tryptophan esters hydrochloride that white solid product, which is obtained by filtration,.
Preferably, in purification described in the preparation method step 2) of this tryptophan esters hydrochloride, the quality of hydrochloric acid is dense
Degree is 7%~15%.
Preferably, in purification described in the preparation method step 2) of this tryptophan esters hydrochloride, by the use of tryptophan
The amount ratio of meter, hydrochloric acid and tryptophan is (1~10) mL:1g.
In the present invention, when the use of paratoluensulfonyl chloride, methanol, tryptophan being prepared by raw material, color ammonia is obtained through step 1)
Acid methyl ester hydrochloride salt crude product, what is obtained through step 2) is tryptophan methyl ester hydrochloride;By alcohol used be ethyl alcohol when, correspondence obtain
Be tryptophan carbethoxy hydrochloride crude product and tryptophan carbethoxy hydrochloride;When by alcohol used being normal propyl alcohol, it is corresponding obtain be
Tryptophan n-propyl hydrochloride, crude and tryptophan n-propyl hydrochloride;When by alcohol used being n-butanol, it is corresponding obtain be
Tryptophan N-butyl hydrochloride, crude and tryptophan N-butyl hydrochloride.
The beneficial effects of the present invention are:
The method that the present invention prepares tryptophan esters hydrochloride is easy to get with market and cheap paratoluensulfonyl chloride, low
Grade alcohol is as raw material, and reaction condition is easily achieved, and easy to operate, cost is substantially reduced with respect to other methods, obtained product
Purity is high is suitble to large-scale industrial production.
Specifically, the invention has the following advantages that
1) the present invention selection stable paratoluensulfonyl chloride that is easy to get, rather than the chlorination of gas chlorination hydrogen and hyperactivity
Sulfoxide;2) tryptophan esters hydrochloride can be directly made using paratoluensulfonyl chloride in the present invention, rather than tryptophan esters pair
Toluene fulfonate;3) amino acid can be used directly in preparation method of the invention, rather than has the amino acid of protecting group, makes operation more
Add simple.
Detailed description of the invention
Fig. 1 is preparation method synthetic line schematic diagram of the invention;
Fig. 2 is the L-Trp methyl ester hydrochloride infrared spectrum that embodiment 1 obtains;
Fig. 3 is the L-Trp methyl ester hydrochloride mass spectrogram that embodiment 1 obtains;
Fig. 4 is the D-trp methyl ester hydrochloride mass spectrogram that embodiment 2 obtains;
Fig. 5 is the L-Trp carbethoxy hydrochloride infrared spectrum that embodiment 3 obtains;
Fig. 6 is the L-Trp n-propyl hydrochloride infrared spectrum that embodiment 4 obtains;
Fig. 7 is the L-Trp N-butyl hydrochloride infrared spectrum that embodiment 5 obtains.
Specific embodiment
Attached drawing 1 is preparation method synthetic line schematic diagram of the invention.ROH in Fig. 1 indicates alcohol.
Referring to Fig. 1, the contents of the present invention are described in further detail by specific embodiment.In embodiment
Raw material used unless otherwise specified, can be obtained from routine business approach.
Embodiment 1
A kind of preparation method of L-Trp methyl ester hydrochloride, comprising the following steps:
5.000g paratoluensulfonyl chloride is added in 100mL flask, 80mL methanol is added, 1.0211g L- color is added after stirring
Propylhomoserin and 40mL methanol are heated at reflux to 70 DEG C of reaction 10h, and revolving removes methanol and tryptophan methyl ester hydrochloride crude product is precipitated.
Crude product and ethyl acetate are mixed, aqueous sodium carbonate is added in stirring, and pH=10 is adjusted, is extracted with ethyl acetate product 3 times,
Organic phase merges, and the hydrochloric acid of mass concentration 10% is added dropwise into organic phase to there is muddiness, is further continued for that hydrochloric acid, hydrochloric acid is added dropwise
Total dosage is 5mL.Filtering, obtains white powder L-Trp methyl ester hydrochloride 1.017g, yield 80%.Yield is according to reality
Obtained product quality is calculated divided by theoretical yield.Through detecting, the HPLC purity of product is 99.45% (area normalization
Method).
The infrared spectrum of product L-Trp methyl ester hydrochloride made from this example is shown in that attached drawing 2, mass spectrogram are shown in attached drawing 3.Through examining
It surveys, the fusing point of L-Trp methyl ester hydrochloride is 197~202 DEG C, 1H NMR
(400MHz, Deuterium Oxide) δ 7.69 (d, J=8.0Hz, 1H), 7.61 (d, J=8.2Hz, 1H), 7.47-7.31 (m,
2H), 7.31-7.21 (m, 1H), 4.53 (t, J=6.3Hz, 1H), 3.88 (s, 3H), 3.66-3.46 (m, 2H).13C NMR
(101MHz,MeOD)δ170.81(s,1H),138.29(s,1H),128.24(s,1H),125.75(s,2H),122.96(s,
2H),120.34(s,2H),118.88(s,2H),112.72(s,2H),107.46(s,1H),54.64(s,2H),53.64(s,
1H),27.54(s,2H)。
Embodiment 2
A kind of preparation method of D-trp methyl ester hydrochloride, comprising the following steps:
2.000g paratoluensulfonyl chloride and 50mL methanol is added in 250mL flask, be added after stirring 2.000g D-trp and
60mL methanol is heated at reflux to 65 DEG C of reaction 12h, and revolving removes methanol and obtains tryptophan methyl ester hydrochloride crude product.It will slightly produce
Product are mixed with methylene chloride, and sodium bicarbonate aqueous solution is added in stirring, are adjusted pH=8, are extracted with dichloromethane product 3 times, organic
Mutually merge, the hydrochloric acid of mass concentration 10% is added dropwise into organic phase to there is muddiness, is further continued for that hydrochloric acid is added dropwise, hydrochloric acid is always used
Amount is 8mL.Filtering, white solid D-trp methyl ester hydrochloride 0.866g, yield 68%.Through detecting, the HPLC of product is pure
Degree is 96.78% (area normalization method).
The mass spectrogram of product D-trp methyl ester hydrochloride made from this example is shown in attached drawing 4.
Embodiment 3
A kind of preparation method of L-Trp carbethoxy hydrochloride, comprising the following steps:
2.5000g paratoluensulfonyl chloride is added in 100mL flask, 100mL ethyl alcohol is added, 2.000g L- is added after stirring
Tryptophan and 60mL ethyl alcohol are heated at reflux to 81 DEG C of reaction 16h, and revolving removes ethyl alcohol precipitation tryptophan carbethoxy hydrochloride and slightly produces
Product.Crude product is mixed with methylene chloride, aqueous sodium carbonate is added in stirring, adjusts pH=9, product 3 is extracted with ethyl acetate
Secondary, organic layer merges, and the hydrochloric acid of mass concentration 8% is added dropwise into organic phase to there is muddiness, is further continued for that hydrochloric acid, salt is added dropwise
Sour total dosage is 9mL.Filtering, obtains white powder L-Trp carbethoxy hydrochloride, yield 54%.
The infrared spectrum of product L-Trp carbethoxy hydrochloride made from this example is shown in attached drawing 5.Through detecting, L-Trp ethyl ester
The fusing point of hydrochloride is 199~201 DEG C,1H NMR(400MHz,D2O) δ 7.64 (d, J=7.8Hz, 1H), 7.55 (d, J=
8.2Hz, 1H), 7.31 (dd, J=14.5,5.7Hz, 2H), 7.22 (t, J=7.4Hz, 1H), 4.44 (t, J=5.8Hz, 1H),
4.24 (q, J=7.1Hz, 2H), 3.49 (d, J=4.3Hz, 2H), 1.22 (t, J=7.1Hz, 3H).13C NMR(101MHz,
MeOD)δ170.40(s,1H),138.26(s,1H),128.30(s,1H),125.69(s,1H),122.94(s,2H),120.24
(s, 2H), 118.92 (s, 2H), 112.70 (s, 2H), 107.58 (s, 1H), 63.63 (s, 2H), 54.75 (d, J=8.8Hz,
2H), 27.65 (d, J=5.3Hz, 2H), 14.23 (s, 2H).
Embodiment 4
A kind of preparation method of L-Trp n-propyl hydrochloride, comprising the following steps:
10.000g paratoluensulfonyl chloride is added in 100mL flask, 150mL normal propyl alcohol is added, 1.0000g is added after stirring
L-Trp and 50mL normal propyl alcohol are heated at reflux to 96 DEG C of reaction 10h, and revolving removes normal propyl alcohol and tryptophan n-propyl hydrochloric acid is precipitated
Salt crude product.Crude product is mixed with ethyl acetate, aqueous sodium carbonate is added in stirring, adjusts pH=11, is extracted and is produced with ether
Product 3 times, organic layer merges, and the hydrochloric acid of mass concentration 12% is added dropwise into organic phase to there is muddiness, is further continued for that salt is added dropwise
Acid, the total dosage of hydrochloric acid are 5mL.Filtering, obtains white powder L-Trp n-propyl hydrochloride, yield 55%.
The infrared spectrum of product L-Trp n-propyl hydrochloride made from this example is shown in attached drawing 6.Through detecting, L-Trp is just
The fusing point of propyl ester hydrochloride is 217~219 DEG C, 1H NMR(400MHz,D2O)δ7.64
(d, J=7.9Hz, 1H), 7.56 (d, J=8.1Hz, 1H), 7.44-7.27 (m, 2H), 7.22 (t, J=7.4Hz, 1H), 4.46
(t, J=6.3Hz, 1H), 4.14 (d, J=3.8Hz, 2H), 3.51 (d, J=6.1Hz, 2H), 1.60 (dd, J=14.1,
7.0Hz, 2H), 0.83 (t, J=7.4Hz, 3H).13C NMR(101MHz,MeOD)δ170.44(s,1H),138.20(s,1H),
128.20 (s, 1H), 125.53 (s, 1H), 122.82 (d, J=6.3Hz, 2H), 120.14 (s, 2H), 118.80 (s, 2H),
112.61 (s, 2H), 107.52 (s, 1H), 68.94 (d, J=12.2Hz, 2H), 54.67 (d, J=9.4Hz, 2H), 27.68 (d,
J=5.5Hz, 2H), 22.63 (s, 2H), 10.42 (s, 2H).
Embodiment 5
A kind of preparation method of L-Trp N-butyl hydrochloride, comprising the following steps:
2.0000g paratoluensulfonyl chloride is added in 100mL flask, 80mL n-butanol is added, 2.000g L- is added after stirring
Tryptophan and 60mL n-butanol are heated at reflux to 127 DEG C of reaction 20h, and revolving removes n-butanol and tryptophan N-butyl hydrochloric acid is precipitated
Salt crude product.Crude product is mixed with methylene chloride, aqueous sodium carbonate is added in stirring, adjusts pH=9, is extracted with dichloromethane
Product 3 times, organic layer merges, and the hydrochloric acid of mass concentration 10% is added dropwise into organic phase to there is muddiness, is further continued for being added dropwise
Hydrochloric acid, the total dosage of hydrochloric acid are 8mL.Filtering, obtains white powder L-Trp N-butyl hydrochloride, yield 56%.
The infrared spectrum of product L-Trp N-butyl hydrochloride made from this example is shown in attached drawing 7.Through detecting, L-Trp is just
The fusing point of propyl ester hydrochloride is 195~200 DEG C, 1H NMR(400MHz,D2O)δ7.62
(d, J=7.9Hz, 1H), 7.56 (d, J=8.2Hz, 1H), 7.38-7.27 (m, 2H), 7.21 (t, J=7.5Hz, 1H), 4.44
(t, J=6.4Hz, 1H), 4.17 (t, J=6.5Hz, 2H), 3.48 (d, J=6.4Hz, 2H), 1.64-1.45 (m, 2H), 1.21
(dd, J=15.0,7.5Hz, 2H), 0.85 (t, J=7.4Hz, 3H).
Claims (10)
1. a kind of preparation method of tryptophan esters hydrochloride, it is characterised in that: the following steps are included:
1) paratoluensulfonyl chloride and tryptophan are reacted in alcohol, obtains tryptophan ester hydrochloride crude product;
2) tryptophan ester hydrochloride crude product is purified, tryptophan esters hydrochloride is obtained.
2. a kind of preparation method of tryptophan esters hydrochloride according to claim 1, it is characterised in that: in step 1),
The dosage of paratoluensulfonyl chloride, tryptophan and alcohol is 1g:(0.1~2) g:(10~100) mL.
3. a kind of preparation method of tryptophan esters hydrochloride according to claim 1, it is characterised in that: in step 1),
Further include the steps that removing extra alcohol.
4. a kind of preparation method of tryptophan esters hydrochloride according to claim 3, it is characterised in that: in step 1),
The method of alcohol is removed as any one in rotary evaporation, volatilization, vacuum distillation.
5. a kind of preparation method of tryptophan esters hydrochloride according to any one of claims 1 to 4, it is characterised in that:
In step 1), alcohol is selected from C1~C10 alcohol.
6. a kind of preparation method of tryptophan esters hydrochloride according to claim 5, it is characterised in that: in step 1),
The temperature of reaction is room temperature~130 DEG C, and the time of reaction is 4h~20h.
7. a kind of preparation method of tryptophan esters hydrochloride according to claim 1, it is characterised in that: in step 2),
Purification is specifically to mix tryptophan ester hydrochloride crude product and organic solvent, and lye is added and adjusts the pH of mixed liquor to alkalinity, so
Organic phase and mixed in hydrochloric acid are extracted afterwards, and filtering obtains tryptophan esters hydrochloride.
8. a kind of preparation method of tryptophan esters hydrochloride according to claim 7, it is characterised in that: step 2) is described
Purification in, adjust the pH of mixed liquor and refer to alkalinity and adjust pH value to 8~11.
9. a kind of preparation method of tryptophan esters hydrochloride according to claim 7, it is characterised in that: step 2) is described
Purification in, organic solvent be esters solvent, ketones solvent, ether solvent, amide solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon
At least one of class solvent, nitrile solvents.
10. a kind of preparation method of tryptophan esters hydrochloride according to claim 7, it is characterised in that: step 2) institute
In the purification stated, the mass concentration of hydrochloric acid is 7%~15%.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103848750A (en) * | 2014-04-08 | 2014-06-11 | 江苏斯威森生物医药工程研究中心有限公司 | Method for preparing alpha-cycloalanine |
CN107106449A (en) * | 2014-12-18 | 2017-08-29 | 欧莱雅 | The ester derivant of tryptophan as deodorant and/or flavouring agent purposes |
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2019
- 2019-08-06 CN CN201910721853.7A patent/CN110483363A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103848750A (en) * | 2014-04-08 | 2014-06-11 | 江苏斯威森生物医药工程研究中心有限公司 | Method for preparing alpha-cycloalanine |
CN107106449A (en) * | 2014-12-18 | 2017-08-29 | 欧莱雅 | The ester derivant of tryptophan as deodorant and/or flavouring agent purposes |
Non-Patent Citations (3)
Title |
---|
ISAMU ARAI ET AL.: "A Simple and Convenient Method for Esterification of Tryptophan and Other Amino Acids", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
周骏山: "《实用氨基酸手册》", 31 December 1989 * |
宋兆成 等: "《有机化学》", 28 February 2003 * |
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