CN113816972B - Preparation method of HIV inhibitor and intermediate crystal form thereof - Google Patents

Preparation method of HIV inhibitor and intermediate crystal form thereof Download PDF

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CN113816972B
CN113816972B CN202111359127.9A CN202111359127A CN113816972B CN 113816972 B CN113816972 B CN 113816972B CN 202111359127 A CN202111359127 A CN 202111359127A CN 113816972 B CN113816972 B CN 113816972B
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CN113816972A (en
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郭万成
张靖达
张富昌
房杰
田鑫
王国平
于振鹏
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Yangzhou Aoruite Pharmaceutical Co ltd
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Abstract

The invention discloses a preparation method of an HIV inhibitor and an intermediate crystal form thereof. The preparation method has high reaction yield and simple post-treatment, and is suitable for industrial production; the intermediate crystal form is higher in yield and purity of a final product obtained by subsequent reaction.

Description

Preparation method of HIV inhibitor and intermediate crystal form thereof
Technical Field
The invention particularly relates to a preparation method of an HIV inhibitor and an intermediate crystal form thereof.
Background
Polycyclic carbamoylpyrimidines derivatives are well known inhibitors of HIV integrase chain transfer and are used in combination with other antiretroviral drugs to treat HIV-1 infections in adults and children over 12 years of age weighing over 40 kg.
Dolutegravir Sodium (Dolutegravir Sodium) was approved by the U.S. Food and Drug Administration (FDA) on 12/8/2013. An anti-AIDS drug developed by Kulansu Schk (GSK) in cooperation with Shionogi, Japan salt wild pharmaceutical company. Is a third FDA-approved HIV integrase inhibitor following Raltegravir (Raltegravir), eltamivir (Elvitegravir). The structural formula is as follows:
Figure 983135DEST_PATH_IMAGE001
。
cabotegravir is an integrase inhibitor and can be administered orally, intramuscularly or subcutaneously. HIV can be effectively inhibited by orally taking 30mg CAB once a day.
Figure 697013DEST_PATH_IMAGE002
Bictegravir is a novel integrase inhibitor developed by Gilead corporation, and unlike previously developed integrase inhibitors, Bictegravir only needs to be used once a day and does not require the synergist cobicistat.
Figure 412556DEST_PATH_IMAGE003
There are several documents currently reporting methods for the preparation of dolutegravir, wherein the preparation method disclosed in WO2010110409 is shown in scheme 1.
Figure 740769DEST_PATH_IMAGE004
The total yield of the route is only 0.5%, especially the reaction yield of the sixth step is only 25%, the product is in the shape of orange powder, the subsequent condensation reaction is directly carried out without purification, the yield is 55%, and the purity of the reaction product of the sixth step is reflected to be not high. Therefore, this route is not suitable for industrial production. The problem of conversion of 7-chloro to 7-hydroxy using silanolate with low yield (25%) is that the process is not suitable for industrialization.
A currently industrially common process is the preparation method disclosed in WO2011119566, as shown in scheme 2:
Figure 539068DEST_PATH_IMAGE004
route 2 uses lithium bromide to remove methyl, the byproduct methyl bromide is a highly toxic gas, and multiple devices are needed to absorb methyl bromide during industrial production to reduce toxicity risk and environmental pollution, thereby greatly increasing industrial cost. The removal of ethyl groups as reported in WO2015110897A2, however, is not high, only 66%.
Therefore, the development of a novel method for preparing the polycyclic carbamoylpyrimidine derivative, which is environment-friendly, has cost advantage and better quality control, is urgently needed in the field.
Disclosure of Invention
The invention aims to solve the problems of low key reaction yield, complex post-treatment, unsuitability for industrialization and the like of a preparation method of an HIV inhibitor in the prior art, and provides a preparation method of the HIV inhibitor and an intermediate crystal form thereof. The preparation method has high reaction yield and simple post-treatment, and is suitable for industrial production; the intermediate crystal form is higher in yield and purity of a final product obtained by subsequent reaction.
The invention provides a preparation method of a compound shown as a formula I, which comprises the following steps:
Figure 54255DEST_PATH_IMAGE006
in tetrahydrofuran, in the presence of lithium bromide, carrying out deprotection reaction on the compound N-3 as shown in the specification to obtain a compound N-2;
Figure 333446DEST_PATH_IMAGE007
；
wherein the deprotection reaction is carried out in the presence of a base or in the absence of a base;
Figure 566981DEST_PATH_IMAGE008
is one or more hydrogens on the phenyl group substituted with F;
n is 0 or 1;
a is methyl and B is hydrogen; or A, B form a five-membered ring structure with the carbon between them;
r is C2~C6An alkyl group;
the alkali is M1OH、
Figure 928692DEST_PATH_IMAGE009
And R1OM2One or more of; m1And M2Independently an alkali metal; r1、R2、R3And R4Independently is C1~C4An alkyl group;
the carbon marked with x is an S configuration or an R configuration chiral carbon.
When n is 0, preferably A is methyl and B is hydrogen.
When n is 1, preferably A is methyl and B is hydrogen.
Or, when n is 1, it is preferable that A, B form a five-membered ring structure with carbon between them.
Said
Figure 171455DEST_PATH_IMAGE008
Preferably, it is
Figure 302222DEST_PATH_IMAGE010
Or
Figure 706658DEST_PATH_IMAGE011
。
C2~C6The alkyl group is preferably C2~C4Alkyl, for example ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl.
When said R is2、R3、R4And R5Independently is C1~C4When alkyl, said C1~C4The alkyl group is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group, for example, an ethyl group.
The alkali metal is preferably one or more of sodium, potassium and cesium.
Said M1The OH can be sodium hydroxide and/or potassium hydroxide.
Said R1OM2Can be BOne or more of sodium alkoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide and potassium methoxide.
Said
Figure 555666DEST_PATH_IMAGE009
May be triethylamine and/or DIPEA.
In a preferred embodiment, A is the same side as the hydrogen on the carbon at position 1.
In a preferred embodiment of the present invention,
Figure 70961DEST_PATH_IMAGE012
is composed of
Figure 321813DEST_PATH_IMAGE010
N is 0, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is
Figure 897151DEST_PATH_IMAGE002
；
In a preferred embodiment of the present invention,
Figure 233455DEST_PATH_IMAGE008
is composed of
Figure 552440DEST_PATH_IMAGE010
When n is 1, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is shown in the specification
Figure 923379DEST_PATH_IMAGE013
；
In a preferred embodiment, n is 1, A, B forms a five-membered ring structure with the carbon between them, and the compound of formula I has the formula
Figure 669618DEST_PATH_IMAGE003
。
The tetrahydrofuran is used in an amount which is conventional in the art for carrying out such reactions, and preferably in a volume molar ratio of 0.5 to 2.0L/mol, for example, 1.21L/mol, to the compound N-3.
When the deprotection reaction is carried out in the presence of a base, the base may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably, the molar ratio thereof to the compound N-3 is 1.0 to 1.5, for example, 1.13.
The amount of lithium bromide may be that conventionally used in the art for such reactions, and is preferably in a molar ratio of 2.5 to 3.5, e.g., 3.02, to compound N-3.
The reaction temperature of the deprotection reaction can be a conventional temperature for carrying out the reaction in the field, and is preferably 50-80 ℃, for example, 60-70 ℃.
The progress of the deprotection reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and is generally determined as the end point of the reaction when compound N-3 is eliminated. The reaction time is preferably 18 to 36 hours, for example, 24 hours.
The deprotection reaction can further comprise post-treatment; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: after the reaction is finished, cooling, adding water to quench the reaction, removing the solvent under reduced pressure, adding dilute hydrochloric acid to precipitate crystals, performing suction filtration to obtain a crude product, drying, and recrystallizing the crude product in acetonitrile/water to obtain the compound N-2.
The preparation method of the compound N-2 can also comprise the following steps: (1) reacting compound N-4 with lithium hydroxide; (2) adding acetic acid and methanesulfonic acid, and continuing to react at 60-80 ℃; (3) cooling to 40-50 ℃, adding triethylamine and a reagent A, and reacting at 70-80 ℃ to obtain a compound N-3; the reagent A is (R) -3-aminobutanol, (S) -2-aminopropanol or
Figure 227638DEST_PATH_IMAGE014
(ii) a Directly carrying out the next reaction in the steps (1) and (2) without any post-treatment;
Figure 350315DEST_PATH_IMAGE015
；
wherein n, A, B and x are as defined above.
The preparation method of the compound shown in the formula I can further comprise the following steps: in dichloromethane, in the presence of a condensing agent, the compounds N-2 and
Figure 310181DEST_PATH_IMAGE016
carrying out condensation reaction as shown in the specification to obtain a compound as shown in a formula I;
Figure 227321DEST_PATH_IMAGE017
；
wherein the content of the first and second substances,
Figure 538217DEST_PATH_IMAGE008
as defined above.
The invention also provides a crystal form of a compound N-2', wherein an X-ray powder diffraction pattern expressed by 2 theta angle by using Cu-Kalpha radiation has characteristic peaks at one or more of the following positions: 7.7o±0.2o，10.3o±0.2o，13.3o±0.2o，14.3o±0.2o，17.8o±0.2o，19.0o±0.2o，20.9o±0.2o，21.9o±0.2o，27.4o±0.2o, 28.5o±0.2o，29.8o±0.2o；
Figure 199005DEST_PATH_IMAGE018
。
Further, the X-ray powder diffraction pattern expressed in terms of 2 θ angles has characteristic peaks at one or more of the following positions: 7.7o±0.2o，10.3o±0.2o，11.5±0.2o，12.8±0.2o，13.3o±0.2o，14.3o±0.2o，15.0 o±0.2o，15.7o±0.2o，16.6o±0.2o，17.5 o±0.2o，17.8o±0.2o，19.1o±0.2o，20.9o±0.2o，21.9o±0.2o，27.4o±0.2o，28.5o±0.2o，29.8o±0.2o。
Further, the X-ray powder diffraction is shown in FIG. 1.
The differential scanning calorimetry diagram of the crystal form of the compound N-2' provided by the invention has an endothermic peak with an initial value of 273.72 ℃ and a peak value of 277.12 ℃.
The Differential Scanning Calorimetry (DSC) chart of the crystal form of the compound N-2' provided by the invention is basically shown in figure 2.
The invention provides a crystal form of compound N-2' with an infrared absorption spectrum at 3455, 3051, 2974, 2889, 1733, 1634, 1544, 1525, 1461, 1451, 1442, 1371, 1304, 1255, 1237, 1215, 1190, 1176, 996, 980, 695, 540cm-1Has an absorption peak.
Furthermore, the invention provides a crystal form of the compound N-2', the infrared absorption spectrum of which is basically shown in figure 4.
The crystal form thermogravimetric analysis (TGA) of the compound N-2' provided by the invention has the weight loss of about 15.1% in the range of 260 ℃ to 310 ℃ and 38.2% in the range of 310 ℃ to 400 ℃.
Still further, the present invention provides a crystalline form of compound N-2' having a thermogravimetric analysis (TGA) substantially as shown in figure 5.
Drawings
FIG. 1 is an XRPD pattern for a typical example of compound N-2'.
FIG. 2 is a DSC of compound N-2'.
FIG. 3 is a drawing of compound N-21HNMR atlas.
FIG. 4 is an IR spectrum of compound N-2'.
FIG. 5 is a TGA profile of Compound N-2'.
Detailed Description
The invention will now be further illustrated by reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The general method comprises the following steps:
XRPD pattern determination method
X-ray powder diffraction instrument: BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source: k α 1=1.54060 a, k α 2=1.54439 a, the strength ratio α 1/α 2 is 0.50000 a; generator (Generator) kv: 30.0 kv; generator (Generator) mA: 10.0 mA; initial 2 θ: 2.000 °, scan range: 2.0000-40.000 degree.
DSC test method
The DSC detector has the model as follows: METTLER TOLEDO DSC1 differential scanning calorimeter; temperature rising procedure: the starting temperature was 25 ℃, increased to 400 ℃ at 10 ℃/min, temperature range: 25-400 ℃.
3.1HNMR test method
The model of the nuclear magnetic detector is BRUKERAVANCEIII, 300MHz, and the deuterated reagent is DMSO-d 6.
IR test method
The infrared spectrophotometer is a PerkinElmer Spectrum Two Fourier transform infrared spectrometer; the operation method comprises the following steps: adopting a KBr tabletting method, and scanning the range of 450-4000 cm-1。
TGA test method
The TGA detector is METTLER TOLEDO TGA/DSC1 thermogravimetric analyzer; temperature rising procedure: the initial temperature is 25 ℃, and the temperature is increased to 400 ℃ at the speed of 10 ℃/min; temperature range: 25-400 ℃.
Compound N-5 reference Organic Letters (2015), 17(3), 564-567 was prepared and used directly in the subsequent step reactions.
Preparation of Compound N-5
Figure 278957DEST_PATH_IMAGE019
And (3) putting the compound N-725.0 g in a reaction bottle, cooling to 0-10 ℃, dropwise adding DMFDMA20.5g, returning to room temperature after dropwise adding, and keeping the temperature until the reaction is complete. Adding 50mL of ethanol into the system, cooling to 0-10 ℃, dropwise adding 16.6g of aminoacetaldehyde dimethyl acetal, heating to room temperature after dropwise adding, and keeping the temperature to react until the reaction is complete. And (3) concentrating the system under reduced pressure until no fraction is separated out, adding 10mL of ethanol into the system, cooling to-10-0 ℃, stirring, crystallizing, filtering, leaching a filter cake with 10mL of ethanol, draining, and drying to obtain a compound N-525.8 g, wherein the HPLC purity is 99.5%.
Preparation of compound N-4
Figure 632578DEST_PATH_IMAGE020
And (3) putting the compound N-781.4 g in a reaction bottle, cooling to 0-10 ℃, dropwise adding 66.9g of DMFDMA, after dropwise adding, returning to room temperature, and keeping the temperature until the reaction is complete. Adding 162mL of ethanol into the system, cooling to 0-10 ℃, dropwise adding 55.1g of aminoacetaldehyde dimethyl acetal, heating to room temperature after dropwise adding, and keeping the temperature to react until the reaction is complete. And (3) concentrating the system under reduced pressure until no fraction is separated out, adding 1300mL of ethanol into the system, adding 204.6g of diethyl oxalate, cooling to 0-10 ℃, adding 95.3g of sodium ethoxide in batches, heating to 20-30 ℃ after the addition is finished, and keeping the temperature until the reaction is complete. And (3) cooling the system to 0-10 ℃, dropwise adding 3N hydrochloric acid to adjust the pH of the system to 6-7, concentrating under reduced pressure until no fraction is separated out basically, adding 650mL of ethyl acetate and 400mL of water, stirring for 1 hour, filtering, leaching a filter cake with 160mL of ethyl acetate, filtering a mother solution, separating liquid, and concentrating an organic phase until no fraction is separated out to obtain a compound N-4138.9 g, wherein the HPLC purity is 97.2%.
Preparation of three, dolutegravir sodium
A. The preparation method of the compound N-3' is as follows:
A1. preparation of Compound N-3 from Compound N-5
Figure 165190DEST_PATH_IMAGE021
Adding 27.0g of compound N-5 into 270mL of ethanol, adding 40.9g of diethyl oxalate, cooling to 0-10 ℃, adding 19.1g of sodium ethoxide into the system in batches, and reacting for 5-10 hours under the condition of heat preservation until the reaction is complete. After the reaction is finished, controlling the temperature to be 0-10 ℃, adding 5.1g of lithium hydroxide monohydrate in batches, keeping the temperature to be 0-10 ℃ and reacting for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out basically, adding 150mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 170mL of ethyl acetate, stirring, separating liquid, concentrating an organic phase until no fraction is separated out, adding 120mL of acetonitrile, continuously concentrating until no fraction is separated out, adding 360mL of acetonitrile into the concentrated system, and then adding 33g of acetic acid, adding 7.3g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 7.7g of triethylamine into the system, stirring for 10 minutes after dropwise adding, continuously dropwise adding 11.6g of (R) -3-aminobutanol into the system, heating the system to 70-80 ℃ after dropwise adding, and reacting until the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated, adding 150mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching a filter cake with ethanol, and carrying out vacuum drying on a wet product to obtain 27.8g of a compound N-3', wherein the HPLC purity is 98.7%.
A2. Preparation of Compound N-3' from Compound N-4
Figure 629670DEST_PATH_IMAGE022
Adding 34.7g of compound N-4 into 170mL of ethanol, cooling the system to 0-10 ℃, adding 5.1g of lithium hydroxide monohydrate in batches, keeping the temperature at 0-10 ℃ for reaction for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out basically, adding 150mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 170mL of ethyl acetate, stirring, separating liquid, concentrating an organic phase until no fraction is separated out, adding 120mL of acetonitrile, continuously concentrating until no fraction is separated out, adding 360mL of acetonitrile into the concentrated system, and then adding 33g of acetic acid, adding 7.3g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 7.7g of triethylamine into the system, stirring for 10 minutes after dropwise adding, continuously dropwise adding 11.6g of (R) -3-aminobutanol into the system, heating the system to 70-80 ℃ after dropwise adding, and reacting until the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated, adding 150mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching a filter cake with ethanol, and carrying out vacuum drying on a wet product to obtain 27.8g of a compound N-3', wherein the HPLC purity is 98.7%.
B. The compound N-2' is prepared as follows:
Figure 298548DEST_PATH_IMAGE023
adding 140g of compound N-3' into 520mL of tetrahydrofuran, cooling to 0-10 ℃, adding 33g of sodium ethoxide in batches, adding 113g of lithium bromide in batches, heating to 60-70 ℃, keeping the temperature, reacting completely, cooling, adding 700mL of water into the system, concentrating under reduced pressure until no fraction is separated out, adding 3N hydrochloric acid dropwise into the system to adjust the pH value of the system to 3-4, and stirring for crystallization. And (4) carrying out suction filtration, and drying the crude product in a vacuum drying oven to obtain a crude product of the compound N-2'. And adding the crude product into a system of 700mL acetonitrile/water (acetonitrile/water =1v/1 v), heating to 70-80 ℃, preserving heat, stirring for 3 hours, cooling to room temperature, carrying out suction filtration, washing a filter cake, and then transferring the filter cake into a vacuum drying oven for drying to obtain 110.2g of a compound N-2', wherein the HPLC purity is 99.3%.
The high-purity compound N-2 'is prepared by changing the types of the solvent, the base and the Lewis acid reagent and further using the compound N-3' in the presence of the Lewis acid reagent while keeping the mole number of each substance unchanged. Some of the conditions screened in the preparation of compound N-2' are shown in Table 1:
TABLE 1
Figure 823071DEST_PATH_IMAGE024
XRPD test is carried out on the obtained compound N-2', the X-ray powder diffraction data is shown in the table 2, and the X-ray powder diffraction pattern is shown in the figure 1; performing DSC test, and the spectrum is shown in figure 2; performing H NMR test, wherein the spectrogram is shown in figure 3; performing an IR test, wherein the spectrogram is shown in FIG. 4; TGA testing was performed and the spectrum is shown in figure 5.
TABLE 2
Figure 842979DEST_PATH_IMAGE025
C. The preparation method of the compound N-1' is as follows:
Figure 845570DEST_PATH_IMAGE026
adding 85.0g of compound N-2' into 500mL of dichloromethane, adding 56.4g of CDI, heating to reflux, keeping the temperature for 4 hours, cooling to 0-10 ℃, dropwise adding 58.1g of 2, 4-difluorobenzylamine, and after dropwise adding, returning the temperature to room temperature for reaction until the reaction is finished. And adding 170mL of 3N hydrochloric acid into the reacted system, stirring for 0.5-1 hour, separating liquid, washing an organic phase with 170mL of 3% sodium bicarbonate solution, washing with 170mL of water, separating liquid, and concentrating the organic phase until no fraction is separated. Adding 470mL of ethanol into the system, heating to 60-70 ℃, keeping the temperature, stirring for 3-4 hours, cooling to 0-10 ℃, stirring for 1-2 hours, performing suction filtration, leaching a filter cake with 170mL of ethanol, and drying a wet product in a vacuum drying oven to obtain 113.9g of a compound N-1', wherein the HPLC purity is 99.7%.
D. Compound N was prepared as follows:
Figure 634535DEST_PATH_IMAGE027
adding 50g of compound N-1' into 400mL of solvent with ethanol/water =4/1, heating to 70-75 ℃, dropwise adding 25.0g of 20% sodium hydroxide solution, stirring at a constant temperature for 1-3 hours after dropwise adding, cooling to room temperature, stirring for 1-3 hours, performing suction filtration, leaching a filter cake with 100mL of ethanol, transferring a wet product into a vacuum drying oven for drying, and obtaining 47.2g of compound N with the HPLC purity of 99.8%.
Preparation of Cabotegravir
A. The preparation method of the compound N-3 '' is as follows:
Figure 592608DEST_PATH_IMAGE028
adding 21.6g of compound N-5 into 220mL of ethanol, adding 32.7g of diethyl oxalate, cooling to 0-10 ℃, adding 15.3g of sodium ethoxide into the system in batches, and reacting for 5-10 hours under the condition of heat preservation until the reaction is complete. After the reaction is finished, controlling the temperature to be 0-10 ℃, adding 4.1g of lithium hydroxide monohydrate in batches, keeping the temperature to be 0-10 ℃ and reacting for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out basically, adding 110mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 110mL of ethyl acetate, stirring, separating liquid, concentrating an organic phase until no fraction is separated out, adding 110mL of acetonitrile, continuously concentrating until no fraction is separated out, adding 280mL of acetonitrile into the concentrated system, then adding 26.4g of acetic acid, adding 5.8g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 6.2g of triethylamine into the system, stirring for 10 minutes after dropwise adding, continuously dropwise adding 7.8g of (S) -2-aminopropanol into the system, and heating the system to 70-80 ℃ after dropwise adding until the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated out, adding 110mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching filter cake with ethanol, and carrying out vacuum drying on wet products to obtain 22.3g of a compound N-3 '', wherein the HPLC purity is 98.8%.
B. The preparation method of the compound N-2 '' is as follows:
Figure 834233DEST_PATH_IMAGE029
adding 20g of compound N-3 '' into 100mL of tetrahydrofuran, adding 4.7g of sodium ethoxide, adding 16.1g of lithium bromide, heating to 60-70 ℃ for reacting for 24 hours, cooling, adding 100mL of water into the system, concentrating under reduced pressure until no fraction is separated out, dropwise adding 3N hydrochloric acid into the system to adjust the pH of the system to 3-4, and crystallizing. And (5) carrying out suction filtration, and drying the crude product in a vacuum drying oven to obtain a crude compound N-2 ''. And adding the crude product into a system of 100mL acetonitrile/water (acetonitrile/water =1v/1 v), heating to 70-80 ℃, preserving heat, stirring for 3 hours, cooling to room temperature, performing suction filtration, washing a filter cake, and drying in a vacuum drying oven to obtain 16.9g of a compound N-2', wherein the HPLC purity is 99.3%.
Preparation of cabotegravir
Figure 640515DEST_PATH_IMAGE030
Adding 28.0g of compound N-2 '' into 140mL of dichloromethane, adding 19.4g of CDI, heating to reflux, keeping the temperature for 4 hours, cooling to 0-10 ℃, dropwise adding 17.2g of 2, 4-difluorobenzylamine, and after dropwise adding, returning the temperature to room temperature for reaction until the reaction is finished. And adding 56mL of 3N hydrochloric acid into the reacted system, stirring for 0.5-1 hour, separating liquid, washing an organic phase with 56mL of 3% sodium bicarbonate solution, washing with 56mL of water, separating liquid, and concentrating the organic phase until no fraction is separated. Adding 140mL of ethanol into the system, heating to 60-70 ℃, keeping the temperature, stirring for 3-4 hours, cooling to 0-10 ℃, stirring for 1-2 hours, performing suction filtration, leaching a filter cake with 56mL of ethanol, and drying a wet product in a vacuum drying oven to obtain 37.2g of a compound N-1 '', wherein the HPLC purity is 98.9%.
Preparation of Bictegravir
A. Preparation of Compound N-3' ″
Figure 549565DEST_PATH_IMAGE031
Adding 19.6g of compound N-5 into 200mL of ethanol, adding 29.7g of diethyl oxalate, cooling to 0-10 ℃, adding 13.4g of sodium ethoxide into the system in batches, and reacting for 5-10 hours under the condition of heat preservation until the reaction is complete. After the reaction is finished, controlling the temperature to be 0-10 ℃, adding 3.7g of lithium hydroxide monohydrate in batches, keeping the temperature at 0-10 ℃ for reaction for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is obtained basically, adding 100mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 170mL of ethyl acetate, stirring, separating liquid, concentrating the organic phase until no fraction is obtained, adding 120mL of acetonitrile, continuously concentrating until no fraction is obtained, adding 150mL of acetonitrile into the concentrated system, then adding 20.4g of acetic acid, adding 4.6g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction to be basically complete, cooling to 40-50 ℃, adding 5.6g of triethylamine into the system dropwise, stirring for 10 minutes after the dropwise addition is finished, continuously adding dropwise into the system
Figure 150311DEST_PATH_IMAGE032
8.2g, after dripping, heating the system to 70-80 ℃ for reaction till the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated out, adding 100mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching filter cake with ethanol, and carrying out vacuum drying on wet products to obtain 16.7g of a compound N-3 ' ' ', wherein the HPLC purity is 99.0%.
B. The compound N-2 ' ' ' is prepared as follows:
Figure 144812DEST_PATH_IMAGE033
adding 15g of compound N-3 ' ' ' into 45mL of tetrahydrofuran, adding 3.1g of sodium ethoxide, adding 11.7g of lithium bromide, heating to 60-70 ℃ for reacting for 24 hours, cooling, adding 75mL of water into the system, concentrating under reduced pressure until no fraction is separated, dropwise adding 3N hydrochloric acid into the system to adjust the pH of the system to 3-4, and crystallizing. And (5) carrying out suction filtration, and drying the crude product in a vacuum drying oven to obtain a crude compound N-2 ' ' '. Adding the crude product into a system of 75mL acetonitrile/water (acetonitrile/water =1v/1 v), heating to 70-80 ℃, preserving heat, stirring for 3 hours, cooling to room temperature, performing suction filtration, washing a filter cake, and drying in a vacuum drying oven to obtain 12.4g of a compound N-2 ' ' ', wherein the yield is as follows: 90.2% and an HPLC purity of 99.2%.
C. Preparation of Bictegravir
Figure 489206DEST_PATH_IMAGE034
Adding 10.0g of compound N-2 ' ' ' into 50mL of dichloromethane, adding 6.3g of CDI, heating to reflux, keeping the temperature for 4 hours, cooling to 0-10 ℃, dropwise adding 6.9g of 2, 4, 6-trifluorobenzylamine, and after dropwise adding, returning the temperature to room temperature for reaction until the reaction is finished. And adding 20mL of 3N hydrochloric acid into the reacted system, stirring for 0.5-1 hour, separating liquid, washing an organic phase with 20mL of 3% sodium bicarbonate solution, washing with 20mL of water, separating liquid, and concentrating the organic phase until no fraction is separated. Adding 50mL of ethanol into the system, heating to 60-70 ℃, keeping the temperature, stirring for 3-4 hours, cooling to 0-10 ℃, stirring for 1-2 hours, performing suction filtration, leaching a filter cake with 20mL of ethanol, and drying a wet product in a vacuum drying oven to obtain 13.7g of a compound N-1 ' ' ', wherein the HPLC purity is 99.4%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A preparation method of a compound shown as a formula I is characterized by comprising the following steps:
Figure 736104DEST_PATH_IMAGE001
；
in tetrahydrofuran, in the presence of lithium bromide, carrying out deprotection reaction on the compound N-3 as shown in the specification to obtain a compound N-2;
Figure 408873DEST_PATH_IMAGE002
(ii) a And
in dichloromethane, in the presence of a condensing agent, the compounds N-2 and
Figure 179383DEST_PATH_IMAGE004
carrying out condensation reaction as shown in the specification to obtain a compound as shown in a formula I;
Figure 805536DEST_PATH_IMAGE005
；
wherein the deprotection reaction is carried out in the presence of a base;
Figure 786131DEST_PATH_IMAGE006
is one or more hydrogens on the phenyl group substituted with F;
n is 0 or 1;
a is methyl and B is hydrogen; or A, B form a five-membered ring structure with the carbon between them;
r is C2~C6An alkyl group;
the base is R1OM2(ii) a And said R is1OM2Is one or more of sodium ethoxide and potassium ethoxide;
the carbon marked with x is an S configuration or an R configuration chiral carbon.
2. The method according to claim 1, wherein the reaction mixture,
when n is 0, A is methyl and B is hydrogen;
or, when n is 1, A is methyl and B is hydrogen;
or, when n is 1, A, B forms a five-membered ring structure with the carbon between them.
3. The method of claim 1, wherein R is C2~C4An alkyl group.
4. The method of claim 1, wherein the step of preparing the composition comprises
Figure 359195DEST_PATH_IMAGE006
Is composed of
Figure 515369DEST_PATH_IMAGE007
Or
Figure 905899DEST_PATH_IMAGE008
。
5. The method of claim 1, wherein R is1OM2Is sodium ethoxide.
6. The method of claim 1, wherein A is the same side as the hydrogen on the carbon at position 1.
7. The method according to claim 1, wherein the reaction mixture,
Figure 717998DEST_PATH_IMAGE009
is composed of
Figure 484965DEST_PATH_IMAGE007
N is 0, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is
Figure 761226DEST_PATH_IMAGE010
；
Or the like, or, alternatively,
Figure 932444DEST_PATH_IMAGE006
is composed of
Figure 123516DEST_PATH_IMAGE007
When n is 1, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is shown in the specification
Figure 100700DEST_PATH_IMAGE011
；
Or n is 1, A, B and carbon between them form a five-membered ring structure, the structural formula of the compound shown in formula I is
Figure 169150DEST_PATH_IMAGE012
。
8. The preparation method according to claim 1, wherein the volume molar ratio of the tetrahydrofuran to the compound N-3 is 0.5 to 2.0L/mol;
and/or, when the deprotection reaction is carried out in the presence of a base, the molar ratio of the base to the compound N-3 is 1.0-1.5;
and/or the molar ratio of the lithium bromide to the compound N-3 is 2.5-3.5;
and/or the reaction temperature of the deprotection reaction is 50-80 ℃.
9. The method of claim 1, further comprising the steps of: (1) reacting compound N-4 with lithium hydroxide; (2) adding acetic acid and methanesulfonic acid, and continuing to react at 60-80 ℃; (3) cooling to 40-50 ℃, adding triethylamine and a reagent A, and reacting at 70-80 ℃ to obtain a compound N-3; the reagent A is (R) -3-aminobutanol, (S) -2-aminopropanol or
Figure 573586DEST_PATH_IMAGE013
(ii) a Directly carrying out the next reaction in the steps (1) and (2) without any post-treatment;
Figure 750490DEST_PATH_IMAGE014
；
wherein n, a, B and x are as defined in any one of claims 1 to 7.
10. The method of claim 1, further comprising the steps of: (1) reacting the compound N-5 with diethyl oxalate under alkaline conditions; (2) reacting compound N-4 with lithium hydroxide; (3) adding acetic acid and methanesulfonic acid, and continuing to react at 60-80 ℃; (4) cooling to 40-50 ℃, adding triethylamine and a reagent A, and reacting at 70-80 ℃ to obtain a compound N-3; the reagent A is (R) -3-aminobutanol, (S) -2-aminopropanol or
Figure 203468DEST_PATH_IMAGE015
(ii) a The steps (1), (2) and (3) are directly subjected to the next reaction without any post-treatment;
Figure 782217DEST_PATH_IMAGE016
；
wherein n, a, B and x are as defined in any one of claims 1 to 7.
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