CN114685322B - Growth method of anti-HIV drug intermediate crystal, obtained crystal and application of crystal - Google Patents
Growth method of anti-HIV drug intermediate crystal, obtained crystal and application of crystal Download PDFInfo
- Publication number
- CN114685322B CN114685322B CN202011613178.5A CN202011613178A CN114685322B CN 114685322 B CN114685322 B CN 114685322B CN 202011613178 A CN202011613178 A CN 202011613178A CN 114685322 B CN114685322 B CN 114685322B
- Authority
- CN
- China
- Prior art keywords
- crystal
- formula
- degrees
- compound
- hiv drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 166
- 239000003814 drug Substances 0.000 title claims abstract description 26
- 230000036436 anti-hiv Effects 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 25
- 229940079593 drug Drugs 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000543 intermediate Substances 0.000 claims abstract description 23
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000010586 diagram Methods 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 230000009286 beneficial effect Effects 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000011403 purification operation Methods 0.000 abstract description 5
- 239000007787 solid Substances 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 38
- RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 16
- 238000012512 characterization method Methods 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 239000007788 liquid Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 2
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 description 2
- 229960005107 darunavir Drugs 0.000 description 2
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229960002933 fosamprenavir calcium Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940078552 o-xylene Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UKOMUVPFRFPHDS-UHFFFAOYSA-N 1,4,2-dioxazine Chemical compound O1C=CON=C1 UKOMUVPFRFPHDS-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a growth method of an anti-HIV drug intermediate crystal, the obtained crystal and application thereof, wherein the growth method comprises the following steps: dissolving the raw materials in methanol at 55-65deg.C, filtering, cooling the filtrate to 20-30deg.C at a speed of 0.05-0.15deg.C/min, and separating to obtain crystals; the raw materials are crude anti-HIV drug intermediates; the structure of the anti-HIV drug intermediate is shown as a formula I. The growth method of the anti-HIV drug intermediate crystal is simple and easy to operate, and the prepared compound crystal shown in the formula A is a rod-shaped solid in appearance, thereby being beneficial to the purification operation; the crystal is stable, which is beneficial to reducing impurities generated in the storage process when the next reaction is carried out, and improving the yield and quality of synthesis; in the reaction of further preparing the anti-HIV medicine, the crystal can also obviously improve the reaction rate.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a growth method of an anti-HIV drug intermediate crystal, the obtained crystal and application thereof.
Background
The tert-butyl (2S, 3R) -3-hydroxy-4- (N-isobutyl-4-nitrobenzenesulfonamino) -1-phenylbutane-2-carbamate can be used for preparing anti-HIV medicines such as fosamprenavir calcium, darunavir, amprenavir and the like, and is an important intermediate. The results are shown below:
wherein, the synthetic route of the fosamprenavir calcium is as follows:
wherein, the synthesis route of the amprenavir is shown as follows:
the synthesis route of the darunavir is as follows:
as a key intermediate for preparing various APIs, the stability of the crystalline form of tert-butyl (2 s,3 r) -3-hydroxy-4- (N-isobutyl-4-nitrobenzenesulfonamino) -1-phenylbutane-2-carbamate is advantageous in reducing impurities generated during the next reaction and improving the yield and quality of the synthesis.
Patent WO2006131757 discloses that tert-butyl (2 s,3 r) -3-hydroxy-4- (N-isobutyl-4-nitrobenzenesulfonamino) -1-phenylbutane-2-carbamate needs to be separated, transferred and stored before further reaction, but the crystal form of the product is fibrous in appearance, difficult to filter, easy to leave solvent, difficult to transfer and difficult to handle.
The preparation method of tert-butyl (2S, 3R) -3-hydroxy-4- (N-isobutyl-4-nitrobenzenesulfonamino) -1-phenylbutane-2-carbamate disclosed in patent WO2006131757 is to heat a saturated solution and cool the saturated solution to obtain crystals, or to crystallize the crystals in the cooling process. The stability of the final crystal form is poor.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a growth method of an anti-HIV drug intermediate crystal, the obtained crystal and application thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the invention provides a method for growing an anti-HIV drug intermediate crystal, which is characterized by comprising the following steps:
dissolving the raw materials in methanol at 55-65deg.C, filtering, cooling the filtrate to 20-30deg.C at a speed of 0.05-0.15 deg.C/min, stirring for 2-3 hr, and separating to obtain crystals;
the raw materials are crude anti-HIV drug intermediates;
the structure of the anti-HIV drug intermediate is shown as a formula I:
the growth method of the anti-HIV drug intermediate crystal is simple and easy to operate, and the prepared compound crystal shown in the formula I is a rod-shaped solid in appearance, thereby being beneficial to the purification operation; the crystal is stable, which is beneficial to reducing impurities generated in the storage process when the next reaction is carried out, and improving the yield and quality of synthesis; in the reaction of further preparing the anti-HIV medicine, the crystal can also obviously improve the reaction rate.
The 55-65deg.C may be 55 deg.C, 56 deg.C, 57 deg.C, 58 deg.C, 59 deg.C, 60 deg.C, 61 deg.C, 62 deg.C, 63 deg.C, 64 deg.C or 65 deg.C, etc., and other specific values within this range may be selected, and will not be described here again.
The above 0.05-0.15 ℃/min may be, for example, 0.05 ℃/min, 0.06 ℃/min, 0.07 ℃/min, 0.08 ℃/min, 0.09 ℃/min, 0.10 ℃/min, 0.11 ℃/min, 0.12 ℃/min, 0.13 ℃/min, 0.14 ℃/min or 0.15 ℃/min, and other specific values within the range may be selected, and will not be described in detail herein.
The cooling rate is specifically selected to be 0.05-0.15 deg.c/min because crystallization of the fiber morphology occurs if the rate is further increased.
The above 20-30deg.C may be, for example, 20deg.C, 21deg.C, 22deg.C, 23deg.C, 25deg.C, 26deg.C, 27deg.C, 28deg.C, 29 deg.C or 30deg.C, etc., and other specific values within this range may be selected, and will not be described here again.
Preferably, the mass volume ratio of the raw materials to the methanol is as follows: each 500mg of the raw material is dissolved in 4-12mL (e.g., 4mL, 5mL, 5.5mL, 6mL, 6.5mL, 7mL, 8mL, 9mL, 10mL, 11mL, 12mL, etc.), and other specific values within this range are selectable, and will not be described in detail herein). Preferably, the mass volume ratio of the raw materials to the methanol is as follows: each 500mg of the starting material was dissolved in 4-8mL of methanol. Preferably, the mass volume ratio of the raw materials to the methanol is as follows: each 500mg of the starting material was dissolved in 5.5-6.5mL of methanol.
Preferably, the cooling rate is 0.09-0.11 ℃/min.
Preferably, the filtrate is cooled to 24-26 ℃.
Preferably, the dissolution of the starting material in methanol is carried out at 58-62 ℃.
In a second aspect, the present invention provides a compound crystal a of formula i prepared by the method for growing an anti-HIV drug intermediate crystal, where the compound crystal a of formula i has characteristic diffraction peaks at 8.38±0.2°, 9.44±0.2°, 13.80±0.2°, 16.56±0.2°, 18.82±0.2°, 19.08±0.2°, 19.62±0.2°, and 23.58±0.2° in an X-ray diffraction pattern.
The crystal is a rod-shaped solid in appearance, which is helpful for the purification operation; the crystal is stable, which is beneficial to reducing impurities generated in the process of storage in the next reaction and improving the yield and quality of synthesis.
In a third aspect, the present invention provides a method for preparing an anti-HIV drug intermediate crystal, the method comprising: the compound crystal A of the formula I is heated to 100-170deg.C (e.g. 100deg.C, 110deg.C, 115 deg.C, 120 deg.C, 125 deg.C, 130 deg.C, 140 deg.C, 160 deg.C, 170 deg.C, etc.), preferably 115-125deg.C, to obtain the compound crystal B of the formula I.
The heating temperature is specifically selected to be 100-170 c because the target compound of a specific crystal form cannot be produced if the temperature is further increased or decreased.
In a fourth aspect, the present invention provides a compound crystal B of formula i, which is prepared by the preparation method described above, wherein the compound crystal B of formula i has characteristic diffraction peaks at 7.09±0.2°, 9.55±0.2°, 10.56±0.2°, 11.48±0.2°, 14.08±0.2°, 16.12±0.2°, 17.61±0.2° in an X-ray diffraction pattern.
The crystal is a rod-shaped solid in appearance, which is helpful for the purification operation; the crystal is stable, which is beneficial to reducing impurities generated in the process of storage in the next reaction and improving the yield and quality of synthesis.
In a fifth aspect, the present invention also provides a preparation method of twelve anti-HIV drug intermediate crystals, where the preparation method is as follows: suspending the compound crystal B shown in the formula I in a solvent, wherein the solvent is respectively a first solvent, o-xylene, 2-butanol, N-butanol, acetic acid, 1, 2-dichloroethane, formamide, ethanol, formic acid, 1, 4-dioxypyrimidine, dimethyl sulfoxide and pyridine, standing for 48-96 hours at 20-30 ℃, and separating to obtain a compound crystal C, a crystal D, a crystal E, a crystal F, a crystal G, a crystal H, a crystal I, a crystal J, a crystal K, a crystal L, a crystal M and a crystal N shown in the formula I; the first solvent is any one of n-heptane, toluene or methylene dichloride.
The 48-96h may be, for example, 48h, 55h, 60h, 65h, 70h, 75h, 80h, 85h, 90h or 96h, etc., and other specific values in the range may be selected, which will not be described in detail herein.
Preferably, the suspension is performed at 20-40 ℃, for example, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃,25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 35 ℃, 40 ℃ and the like, and other specific values within the range can be selected, and will not be described in detail herein.
Preferably, the dissolution is carried out at 24-26 ℃.
Preferably, the rest is carried out at 24-26 ℃ for 65-75 hours.
Preferably, the mass-volume ratio of the crystal B to the solvent is: each 50mg of crystal B is dissolved in 0.5-1.5mL (e.g., 0.5mL, 0.6mL, 0.7mL, 0.8mL, 0.9mL, 1.0mL, 1.1mL, 1.2mL, 1.3mL, 1.4mL, 1.5mL, etc.) of the solvent.
Preferably, the mass-volume ratio of the crystal B to the solvent is: each 500mg of crystal B is dissolved in 0.5-1.5mL (e.g., 0.5mL, 0.6mL, 0.7mL, 0.8mL, 0.9mL, 1.0mL, 1.1mL, 1.2mL, 1.3mL, 1.4mL, 1.5mL, etc.) of the solvent.
Twelve different crystal forms of the compound crystal shown in the formula I can be obtained by the preparation method, and the specific steps are as follows:
in a sixth aspect, the present invention provides a compound crystal C of formula i having characteristic diffraction peaks at 6.96±0.2°, 9.98±0.2°, 10.40±0.2°, 11.04±0.2°, 13.92±0.2°, 16.41±0.2°, 17.97±0.2°, 21.11±0.2° in an X-ray diffraction pattern of the compound crystal C of formula i produced by the production process according to the fifth aspect.
In a seventh aspect, the present invention provides a compound crystal D of formula i having characteristic diffraction peaks at 8.68±0.2°, 9.89±0.2°, 15.61±0.2°, 16.07±0.2°, 18.08±0.2°, 20.82±0.2°, 21.69±0.2°, 26.55±0.2° in an X-ray diffraction pattern of the compound crystal D prepared by the preparation method according to the fifth aspect.
In an eighth aspect, the present invention provides a compound crystal E of formula i having characteristic diffraction peaks at 7.30±0.2°, 7.57±0.2°, 8.51±0.2°, 14.56±0.2°, 16.50±0.2°, 18.38±0.2°, 18.75±0.2°, 21.24±0.2° in an X-ray diffraction pattern of the compound crystal E prepared by the preparation method according to the fifth aspect.
In a ninth aspect, the present invention provides a compound crystal F of formula i having characteristic diffraction peaks at 7.32±0.2°, 7.68±0.2°, 8.56±0.2°, 14.64±0.2°, 15.78±0.2°, 16.56±0.2°, 18.94±0.2°, 21.36±0.2° in an X-ray diffraction pattern of the compound crystal F prepared by the preparation method according to the fifth aspect.
In a tenth aspect, the present invention provides a compound crystal G of formula i having characteristic diffraction peaks at 7.96±0.2°, 8.68±0.2°, 10.53±0.2°, 14.30±0.2°, 15.26±0.2°, 16.61±0.2°, 17.40±0.2°, 21.70 ±0.2° in an X-ray diffraction pattern of the compound crystal G prepared by the preparation method according to the fifth aspect.
In an eleventh aspect, the present invention provides a compound crystal H of formula i having characteristic diffraction peaks at 6.38±0.2°, 8.76±0.2°, 9.71±0.2°, 15.93±0.2°, 17.13±0.2°, 18.89±0.2°, 19.96±0.2°, 22.17±0.2° in an X-ray diffraction pattern of the compound crystal H prepared by the preparation method according to the fifth aspect.
In a twelfth aspect, the present invention provides a compound crystal I of formula I produced by the production method according to the fifth aspect, wherein the compound crystal I of formula I has characteristic diffraction peaks at 6.95±0.2°, 8.45±0.2°, 9.56±0.2°, 10.44±0.2°, 13.95±0.2°, 15.20±0.2°, 17.00±0.2°, 17.47±0.2° in an X-ray diffraction pattern.
In a thirteenth aspect, the present invention provides a compound crystal J of formula i having characteristic diffraction peaks at 7.29±0.2°, 7.55±0.2°, 7.76±0.2°, 8.57±0.2°, 14.64±0.2°, 15.77±0.2°, 16.59±0.2°, 19.01 ±0.2° in an X-ray diffraction pattern of the compound crystal J produced by the production method according to the fifth aspect.
In a fourteenth aspect, the present invention provides a compound crystal K of formula i having characteristic diffraction peaks at 7.52±0.2°, 8.26±0.2°, 9.36±0.2°, 15.16±0.2°, 16.64±0.2°, 19.23±0.2°, 19.76±0.2°, 23.46±0.2° in an X-ray diffraction pattern of the compound crystal K prepared by the preparation method according to the fifth aspect as defined in claim 6.
In a fifteenth aspect, the present invention provides a compound crystal L of formula i having characteristic diffraction peaks at 6.39±0.2°, 9.53±0.2°, 10.00±0.2°, 15.86±0.2°, 16.51±0.2°, 18.29±0.2°, 19.30±0.2°, 21.24±0.2° in an X-ray diffraction pattern of the compound crystal L prepared by the preparation method according to the fifth aspect.
In a sixteenth aspect, the present invention provides a compound crystal M of formula i having characteristic diffraction peaks at 6.27±0.2°, 10.68±0.2°, 12.32±0.2°, 14.99±0.2°, 18.47±0.2°, 20.34±0.2°, 25.44±0.2°, 26.26 ±0.2° in an X-ray diffraction pattern of the compound crystal M prepared by the preparation method according to the fifth aspect.
In a seventeenth aspect, the present invention provides a compound crystal N of formula i having characteristic diffraction peaks at 7.56±0.2°, 8.78±0.2°, 10.68±0.2°, 12.66±0.2°, 14.46±0.2°, 15.98±0.2°, 17.77 ±0.2°, 18.52±0.2° in an X-ray diffraction pattern of the compound crystal N prepared by the preparation method according to the fifth aspect.
Compared with the prior art, the invention has the following beneficial effects:
the growth method of the anti-HIV drug intermediate crystal is simple and easy to operate, and the prepared compound crystal shown in the formula I is a rod-shaped solid in appearance, thereby being beneficial to the purification operation; the crystal is stable, which is beneficial to reducing impurities generated in the storage process when the next reaction is carried out, and improving the yield and quality of synthesis; in the reaction of further preparing the anti-HIV medicine, the crystal can also obviously improve the reaction rate. The intermediate crystal of the anti-HIV medicine can be used as a raw material to further prepare other thirteen novel intermediate crystals of the compound shown in the formula I, and the crystals also have similar beneficial effects.
Drawings
FIG. 1 is an XRPD pattern for the crystals produced in example 1;
FIG. 2 is a DSC profile of the crystal prepared in example 1;
FIG. 3 is an XRPD pattern for the crystals produced in example 2;
FIG. 4 is a DSC characterization of the crystals produced in example 2;
FIG. 5 is an XRPD pattern for the crystals produced in example 3;
FIG. 6 is a DSC characterization of the crystals produced in example 3;
FIG. 7 is an XRPD pattern for the crystals produced in example 4;
FIG. 8 is a DSC profile of the crystal prepared in example 4;
FIG. 9 is an XRPD pattern for the crystals produced in example 5;
FIG. 10 is a DSC characterization of the crystals produced in example 5;
FIG. 11 is an XRPD pattern for the crystals produced in example 6;
FIG. 12 is a DSC characterization of the crystals produced in example 6;
FIG. 13 is an XRPD pattern for the crystals produced in example 7;
FIG. 14 is a DSC characterization of the crystal prepared in example 7;
FIG. 15 is an XRPD pattern for the crystals produced in example 8;
FIG. 16 is a DSC characterization of the crystal prepared in example 8;
FIG. 17 is an XRPD pattern for the crystals produced in example 9;
FIG. 18 is a DSC characterization of the crystal prepared in example 9;
FIG. 19 is an XRPD pattern for the crystals produced in example 10;
FIG. 20 is a DSC characterization of the crystals produced in example 10;
FIG. 21 is an XRPD pattern for the crystals produced in example 11;
FIG. 22 is a DSC chart of the crystal prepared in example 11;
FIG. 23 is an XRPD pattern for the crystals produced in example 12;
FIG. 24 is a DSC characterization of the crystals produced in example 12;
FIG. 25 is an XRPD pattern for the crystals produced in example 13;
FIG. 26 is a DSC characterization of the crystal prepared in example 13;
FIG. 27 is an XRPD pattern for the crystals produced in example 14;
FIG. 28 is a DSC characterization of the resulting crystal of example 14;
FIG. 29 is a representation of XRPD patterns before and after stability testing of form B;
FIG. 30 is a representation of XRPD patterns before and after stability testing of form C;
FIG. 31 is a DVS plot of form A;
FIG. 32 is a representation of XRPD patterns before and after a form A hygroscopicity test;
FIG. 33 is a DVS plot of form B;
fig. 34 is an XRPD characterization of form B before and after the hygroscopicity test.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The compounds involved in the crystals in the following examples are all compounds of formula I:
the raw materials involved in the following examples are all self-made, and the self-made method is referred to patent WO2008132154.
Example 1
This example provides a crystal of a compound of formula I, prepared as follows:
500mg of the starting material was dissolved in 6mL of methanol at 60℃and filtered. The filtered solution was then cooled to 25℃at a rate of 0.1℃per minute and isolated to give crystals.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 8.38.+ -. 0.2 °, 9.44.+ -. 0.2 °, 13.80.+ -. 0.2 °, 16.56.+ -. 0.2 °, 18.82.+ -. 0.2 °, 19.08.+ -. 0.2 °, 19.62.+ -. 0.2 °, 23.58.+ -. 0.2 °, as shown in fig. 1. Further characterized by DSC, which has two endothermic peaks at-90℃and-174℃respectively, as shown in FIG. 2.
Example 2
This example provides a crystal of a compound of formula I, prepared as follows:
10mg of the crystals of example 1 were placed in a DSC pan and heated to 120℃using DSC.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.09.+ -. 0.2 °, 9.55.+ -. 0.2 °, 10.56.+ -. 0.2 °, 11.48.+ -. 0.2 °, 14.08.+ -. 0.2 °, 16.12.+ -. 0.2 °, 17.61.+ -. 0.2 °, as shown in fig. 3. Further characterized by DSC, it has an endothermic peak at-174℃as shown in FIG. 4.
Example 3-1
This example provides a crystal of a compound of formula I, prepared as follows:
50mg of the crystals of example 2 were suspended in 1mL of n-heptane to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.96.+ -. 0.2 °, 9.98.+ -. 0.2 °, 10.40.+ -. 0.2 °, 11.04.+ -. 0.2 °, 13.92.+ -. 0.2 °, 16.41.+ -. 0.2 °, 17.97.+ -. 0.2 °, 21.11.+ -. 0.2 °, as shown in fig. 5. Further characterized by DSC, it has an endothermic peak at 173 ℃, as shown in figure 6.
Example 3-2
This example provides a crystal of a compound of formula I, prepared as follows:
50mg of the crystals of example 2 were suspended in 1mL of toluene to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.96.+ -. 0.2 °, 9.98.+ -. 0.2 °, 10.40.+ -. 0.2 °, 11.04.+ -. 0.2 °, 13.92.+ -. 0.2 °, 16.41.+ -. 0.2 °, 17.97.+ -. 0.2 °, 21.11.+ -. 0.2 ° as in example 3-1.
Examples 3 to 3
This example provides a crystal of a compound of formula I, prepared as follows:
50mg of the crystals of example 2 were suspended in 1mL of methylene chloride to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.96.+ -. 0.2 °, 9.98.+ -. 0.2 °, 10.40.+ -. 0.2 °, 11.04.+ -. 0.2 °, 13.92.+ -. 0.2 °, 16.41.+ -. 0.2 °, 17.97.+ -. 0.2 °, 21.11.+ -. 0.2 ° as in example 3-1.
Example 4
This example provides a crystal of a compound of formula I, prepared as follows:
50mg of the crystals of example 2 were suspended in 1mL of o-xylene to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 8.68.+ -. 0.2 °, 9.89.+ -. 0.2 °, 15.61.+ -. 0.2 °, 16.07.+ -. 0.2 °, 18.08.+ -. 0.2 °, 20.82.+ -. 0.2 °, 21.69.+ -. 0.2 °, 26.55.+ -. 0.2 °, as shown in fig. 7. Further characterized by DSC, it has three endothermic peaks at 109 ℃, 114 ℃ and 173 ℃, as shown in FIG. 8.
Example 5
This example provides a crystal of a compound of formula I, prepared as follows:
50mg of the crystals of example 2 were suspended in 1mL of 2-butanol to form a suspension, which was magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.30.+ -. 0.2 °, 7.57.+ -. 0.2 °, 8.51.+ -. 0.2 °, 14.56.+ -. 0.2 °, 16.50.+ -. 0.2 °, 18.38.+ -. 0.2 °, 18.75.+ -. 0.2 °, 21.24.+ -. 0.2 °, as shown in fig. 9. Further characterized by DSC, it has two endothermic peaks at 104℃and 173℃as shown in FIG. 10.
Example 6
This example provides a crystal of a compound of formula I, prepared as follows:
50mg of the crystals of example 2 were suspended in 1mL of n-butanol to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.32.+ -. 0.2 °, 7.68.+ -. 0.2 °, 8.56.+ -. 0.2 °, 14.64.+ -. 0.2 °, 15.78.+ -. 0.2 °, 16.56.+ -. 0.2 °, 18.94.+ -. 0.2 °, 21.36.+ -. 0.2 °, as shown in fig. 11. Further characterized by DSC, it has three endothermic peaks at 69 ℃, 100 ℃ and 173 ℃, as shown in FIG. 12.
Example 7
This example provides a crystal of a compound of formula I, prepared as follows:
100mg of the crystals of example 2 were suspended in 1mL of acetic acid to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.96.+ -. 0.2 °, 8.68.+ -. 0.2 °, 10.53.+ -. 0.2 °, 14.30.+ -. 0.2 °, 15.26.+ -. 0.2 °, 16.61.+ -. 0.2 °, 17.40.+ -. 0.2 °, 21.70.+ -. 0.2 °, as shown in fig. 13. Further characterized by DSC, it has three endothermic peaks at 109 ℃, 164 ℃ and 170 ℃, as shown in FIG. 14.
Example 8
This example provides a crystal of a compound of formula I, prepared as follows:
100mg of the crystals of example 2 were suspended in 1mL of 1, 2-dichloroethane to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.38.+ -. 0.2 °, 8.76.+ -. 0.2 °, 9.71.+ -. 0.2 °, 15.93.+ -. 0.2 °, 17.13.+ -. 0.2 °, 18.89.+ -. 0.2 °, 19.96.+ -. 0.2 °, 22.17.+ -. 0.2 °, as shown in fig. 15. Further characterized by DSC, it has two endothermic peaks at 123℃and 173℃as shown in FIG. 16.
Example 9
This example provides a crystal of a compound of formula I, prepared as follows:
100mg of the crystals of example 2 were suspended in 1mL of formamide to form a suspension, which was magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.95.+ -. 0.2 °, 8.45.+ -. 0.2 °, 9.56.+ -. 0.2 °, 10.44.+ -. 0.2 °, 13.95.+ -. 0.2 °, 15.20.+ -. 0.2 °, 17.00.+ -. 0.2 °, 17.47.+ -. 0.2 °, as shown in FIG. 17. Further characterized by DSC, it has three endothermic peaks at 103 ℃, 137 ℃ and 191 ℃, as shown in FIG. 18.
Example 10
This example provides a crystal of a compound of formula I, prepared as follows:
100mg of the crystals of example 2 were suspended in 1mL of ethanol to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.29.+ -. 0.2 °, 7.55.+ -. 0.2 °, 7.76.+ -. 0.2 °, 8.57.+ -. 0.2 °, 14.64.+ -. 0.2 °, 15.77.+ -. 0.2 °, 16.59.+ -. 0.2 °, 19.01.+ -. 0.2 °, as shown in fig. 19. Further characterized by DSC, it has three endothermic peaks at 75 ℃, 106 ℃ and 173 ℃, as shown in FIG. 20.
Example 11
This example provides a crystal of a compound of formula I, prepared as follows:
100mg of the crystals of example 2 were suspended in 1mL of formic acid to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.52.+ -. 0.2 °, 8.26.+ -. 0.2 °, 9.36.+ -. 0.2 °, 15.16.+ -. 0.2 °, 16.64.+ -. 0.2 °, 19.23.+ -. 0.2 °, 19.76.+ -. 0.2 °, 23.46.+ -. 0.2 °, as shown in fig. 21. Further characterized by DSC, it has four endothermic peaks at 88 ℃, 118 ℃, 136 ℃ and 148 ℃ as shown in FIG. 22.
Example 12
This example provides a crystal of a compound of formula I, prepared as follows:
100mg of the crystals of example 2 were suspended in 1mL of 1, 4-dioxapyrimidine to form a suspension, which was magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.39.+ -. 0.2 °, 9.53.+ -. 0.2 °, 10.00.+ -. 0.2 °, 15.86.+ -. 0.2 °, 16.51.+ -. 0.2 °, 18.29.+ -. 0.2 °, 19.30.+ -. 0.2 °, 21.24.+ -. 0.2 °, as shown in fig. 23. Further characterized by DSC, it has three endothermic peaks at 69 ℃, 100 ℃ and 173 ℃, as shown in FIG. 24.
Example 13
This example provides a crystal of a compound of formula I, prepared as follows:
500mg of the crystals of example 2 were suspended in 1mL of dimethylsulfoxide to form a suspension, magnetically stirred at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 6.27.+ -. 0.2 °, 10.68.+ -. 0.2 °, 12.32.+ -. 0.2 °, 14.99.+ -. 0.2 °, 18.47.+ -. 0.2 °, 20.34.+ -. 0.2 °, 25.44.+ -. 0.2 °, 26.26.+ -. 0.2 °, as shown in FIG. 25. Further characterized by DSC, it has two endothermic peaks at 124℃and 174℃as shown in FIG. 26.
Example 14
This example provides a crystal of a compound of formula I, prepared as follows:
500mg of the crystals of example 2 were suspended in 1mL of pyridine to form a suspension, which was left at 25℃for 3 days, and then the residual liquid was separated by filtration.
XRPD (Bruker D2 PHASER diffractometer,2θ, cu-kα) was used to characterize it as: 7.56.+ -. 0.2 °, 8.78.+ -. 0.2 °, 10.68.+ -. 0.2 °, 12.66.+ -. 0.2 °, 14.46.+ -. 0.2 °, 15.98.+ -. 0.2 °, 17.77.+ -. 0.2 °, 18.52.+ -. 0.2 °, as shown in fig. 27. Further characterized by DSC, it has three endothermic peaks at 74 ℃, 104 ℃ and 173 ℃, as shown in FIG. 28.
Evaluation test:
(1) Stability evaluation
The operation method and the result of the evaluation are shown in the following table:
wherein HPLC was used for purity measurement, and the measurement conditions are shown in the following table:
XRPD characterizations before and after form B stability test are shown in fig. 29; XRPD characterizations before and after the form C stability test are shown in figure 30. As can be seen from the figure: the crystal form B, C can keep good stability under various temperature and humidity conditions, the purity is hardly reduced, and the crystal form structure can be kept unchanged.
(2) Evaluation of hygroscopicity
The operation method of the evaluation specifically comprises the following steps:
using ADVENTURE series dynamic gas phase adsorption (DVS) at N 2 The hygroscopicity data of the samples were collected under protection and the sample amount was 30mg.
The test method is as follows:
1) Relative humidity increase process: 0% RH to 90% RH at a rate of 10% RH/stage;
2) Relative humidity reduction process: 90% RH to 0% RH at a rate of 10% RH/stage.
The results are shown in FIGS. 31-34. FIG. 31 is a DVS plot of form A; FIG. 32 is a representation of XRPD patterns before and after a form A hygroscopicity test; FIG. 33 is a DVS plot of form B; fig. 34 is an XRPD characterization of form B before and after the hygroscopicity test.
FIG. 31 shows that form A has a water absorption of 0.46% at 25℃and 80% relative humidity; FIG. 32 shows that the crystals are stable and the crystal form is unchanged; fig. 33 shows that form B has a water absorption of almost 0 at 25 ℃,80% relative humidity; fig. 34 shows that the crystals were stable and the crystal forms were unchanged.
The applicant states that the present invention describes a method for growing an anti-HIV drug intermediate crystal and the resulting crystal and its use by the above examples, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be practiced by relying on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (1)
1. A method for growing an anti-HIV drug intermediate crystal B, which is characterized by comprising the following steps:
dissolving the raw materials in methanol at 58-62 ℃, filtering, cooling the filtrate to 24-26 ℃ at the speed of 0.09-0.11 ℃/min, stirring for 2-3h, separating to obtain a compound crystal A shown in the formula I, and heating the compound crystal A shown in the formula I to 115-125 ℃ to obtain a compound crystal B shown in the formula I;
the raw materials are crude anti-HIV drug intermediates;
the structure of the anti-HIV drug intermediate is shown as a formula I:
the mass volume ratio of the raw materials to the methanol is as follows: dissolving 500mg of the raw material in 5.5-6.5mL of methanol;
in the X-ray diffraction diagram of the compound crystal A shown in the formula I, characteristic diffraction peaks are arranged at 8.38+/-0.2 degrees, 9.44+/-0.2 degrees, 13.80+/-0.2 degrees, 16.56+/-0.2 degrees, 18.82+/-0.2 degrees, 19.08+/-0.2 degrees, 19.62+/-0.2 degrees and 23.58+/-0.2 degrees;
in the X-ray diffraction diagram of the compound crystal B shown in the formula I, characteristic diffraction peaks are arranged at 7.09+/-0.2 degrees, 9.55+/-0.2 degrees, 10.56+/-0.2 degrees, 11.48+/-0.2 degrees, 14.08+/-0.2 degrees, 16.12+/-0.2 degrees and 17.61+/-0.2 degrees.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311034040.3A CN117142989A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal A and crystal obtained by same |
CN202311034147.8A CN118026896A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal and obtained crystal |
CN202011613178.5A CN114685322B (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal, obtained crystal and application of crystal |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011613178.5A CN114685322B (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal, obtained crystal and application of crystal |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311034147.8A Division CN118026896A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal and obtained crystal |
CN202311034040.3A Division CN117142989A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal A and crystal obtained by same |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114685322A CN114685322A (en) | 2022-07-01 |
CN114685322B true CN114685322B (en) | 2023-08-25 |
Family
ID=82131748
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311034147.8A Pending CN118026896A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal and obtained crystal |
CN202311034040.3A Pending CN117142989A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal A and crystal obtained by same |
CN202011613178.5A Active CN114685322B (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal, obtained crystal and application of crystal |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311034147.8A Pending CN118026896A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal and obtained crystal |
CN202311034040.3A Pending CN117142989A (en) | 2020-12-30 | 2020-12-30 | Growth method of anti-HIV drug intermediate crystal A and crystal obtained by same |
Country Status (1)
Country | Link |
---|---|
CN (3) | CN118026896A (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1891698A (en) * | 2005-07-06 | 2007-01-10 | 刘峰岳 | Method forproducing carbamate |
CN1898248A (en) * | 2003-12-23 | 2007-01-17 | 泰博特克药品有限公司 | Process for the preparation of (3r,3as,6ar)-hexahydrofuro [2,3-b] furan-3-yl (1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate |
CN101668734A (en) * | 2007-04-27 | 2010-03-10 | 泰博特克药品有限公司 | The preparation method of N-isobutyl--N-(2-hydroxyl-3-amino-4-phenyl butyl)-right-nitrobenzene sulfonamide derivative |
WO2011061590A1 (en) * | 2009-11-17 | 2011-05-26 | Hetero Research Foundation | Novel carboxamide derivatives as hiv inhibitors |
CN104387299A (en) * | 2014-10-23 | 2015-03-04 | 凯莱英医药集团(天津)股份有限公司 | Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide |
CN104478830A (en) * | 2014-12-31 | 2015-04-01 | 中国医学科学院医药生物技术研究所 | Tertiary amine analogical peptide derivative and application of tertiary amine analogical peptide derivative in inhibiting HIV-1 protease |
CN108409698A (en) * | 2017-02-09 | 2018-08-17 | 中国医学科学院医药生物技术研究所 | Bis- target spot hiv inhibitors of RT/PR and its preparation method and application |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6548706B2 (en) * | 1999-12-23 | 2003-04-15 | Aerojet Fine Chemicals Llc | Preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl) -p-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines |
WO2010077317A2 (en) * | 2008-12-17 | 2010-07-08 | Amplyx Pharmaceuticals, Inc. | Protease inhibitors |
EP2477992B1 (en) * | 2009-09-17 | 2016-12-14 | Mylan Laboratories Limited | Processes for the preparation of darunavir and the amorphous form thereof |
-
2020
- 2020-12-30 CN CN202311034147.8A patent/CN118026896A/en active Pending
- 2020-12-30 CN CN202311034040.3A patent/CN117142989A/en active Pending
- 2020-12-30 CN CN202011613178.5A patent/CN114685322B/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1898248A (en) * | 2003-12-23 | 2007-01-17 | 泰博特克药品有限公司 | Process for the preparation of (3r,3as,6ar)-hexahydrofuro [2,3-b] furan-3-yl (1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate |
CN1891698A (en) * | 2005-07-06 | 2007-01-10 | 刘峰岳 | Method forproducing carbamate |
CN101668734A (en) * | 2007-04-27 | 2010-03-10 | 泰博特克药品有限公司 | The preparation method of N-isobutyl--N-(2-hydroxyl-3-amino-4-phenyl butyl)-right-nitrobenzene sulfonamide derivative |
WO2011061590A1 (en) * | 2009-11-17 | 2011-05-26 | Hetero Research Foundation | Novel carboxamide derivatives as hiv inhibitors |
CN104387299A (en) * | 2014-10-23 | 2015-03-04 | 凯莱英医药集团(天津)股份有限公司 | Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide |
CN104478830A (en) * | 2014-12-31 | 2015-04-01 | 中国医学科学院医药生物技术研究所 | Tertiary amine analogical peptide derivative and application of tertiary amine analogical peptide derivative in inhibiting HIV-1 protease |
CN108409698A (en) * | 2017-02-09 | 2018-08-17 | 中国医学科学院医药生物技术研究所 | Bis- target spot hiv inhibitors of RT/PR and its preparation method and application |
Non-Patent Citations (1)
Title |
---|
Takuya Kanemitsu等.A Concise One-Pot Organo- and Biocatalyzed Preparation of Enantiopure Hexahydrofuro[2,3-b]furan-3-ol: An Approach to the Synthesis of HIV Protease Inhibitors.《Eur. J. Org. Chem.》.2016,1874-1880. * |
Also Published As
Publication number | Publication date |
---|---|
CN117142989A (en) | 2023-12-01 |
CN118026896A (en) | 2024-05-14 |
CN114685322A (en) | 2022-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
CN108794491B (en) | Refining method of tofacitinib citrate | |
KR20080064990A (en) | Process for the preparation of cefdinir | |
JP2000514833A (en) | Crystalline cefdiniramine salt | |
JP2015107976A (en) | Tenofovir disoproxil in crystalline form and method for manufacturing the same | |
CN114685322B (en) | Growth method of anti-HIV drug intermediate crystal, obtained crystal and application of crystal | |
JP2009518412A (en) | A scalable method for preparing rapamycin 42-ester from rapamycin 42-ester boronate | |
WO2009082913A1 (en) | Process for isolation of a mixture of rrrs and sssr configurations of nebivolol intermediates | |
JP2016175938A (en) | Crystallization of epirubicin hydrochloride | |
JP4681545B2 (en) | Method for producing crystalline polymorphs of platelet aggregation inhibitors | |
KR100375957B1 (en) | D4t polymorphic form i process | |
CA3058886C (en) | Method for manufacturing diastereomer of citric acid derivative | |
CA2268586A1 (en) | Process for producing n-glycyltyrosine and its crystal structure | |
JP2007501274A (en) | Cabergoline polymorph | |
KR20120096200A (en) | Crystalline form of docetaxel and process for preparation thereof | |
CN113072454B (en) | Novel crystal form of oxoethylamine compound | |
GB2421024A (en) | Cefdinir crystalline form C | |
CN115536710B (en) | Preparation method of high-quality cytidine sulfate crystal | |
KR20130063521A (en) | Preparation of crystalline form ii of glyceryl phosphoryl choline | |
CN106432197B (en) | Ledipasvir intermediate mono-p-toluenesulfonate, crystal form and preparation method thereof | |
CN112552188B (en) | Preparation method of sertraline hydrochloride crystal form I | |
CN114605416A (en) | Preparation method of acatinib crystal form I | |
US20220315524A1 (en) | Preparation method for salicylamine acetate | |
CN102007132B (en) | Crystalline (6R,7R)-7-{2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-[(z)-trityloxyimino]-acetylamino}-3-[(r)-1'-tert-butoxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-(3E)-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester, preparation and use thereof | |
CN111801313B (en) | Method for preparing polymorphic form B of treprostinil diethanolamine salt |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |